Transcutaneous Electrical Nerve Stimulation Combined with Oxybutynin is Superior to Monotherapy in Children with Urge Incontinence: A Randomized, Placebo Controlled Study.

PURPOSE: We evaluated whether combination therapy with transcutaneous electrical nerve stimulation and oxybutynin results in a superior treatment response compared to either therapy alone in children with urge incontinence. MATERIALS AND METHODS: In this placebo controlled study 66 children with a mean ± SD age of 7.3 ± 1.6 years who were diagnosed with urge incontinence were randomized to 3 treatment groups. Group 1 consisted of 22 children undergoing transcutaneous electrical nerve stimulation plus active oxybutynin administration. Group 2 included 21 children undergoing active transcutaneous electrical nerve stimulation plus placebo oxybutynin administration. Group 3 consisted of 23 children undergoing active oxybutynin administration plus placebo transcutaneous electrical nerve stimulation. The children received active or placebo transcutaneous electrical nerve stimulation over the sacral S2 to S3 outflow for 2 hours daily in combination with 5 mg active or placebo oxybutynin twice daily. The intervention period was 10 weeks. Primary outcome was number of wet days weekly. Secondary outcomes were severity of incontinence, frequency, maximum voided volume over expected bladder capacity for age, average voided volume over expected bladder capacity for age and visual analogue scale score. RESULTS: Combination therapy was superior to oxybutynin monotherapy, with an 83% greater chance of treatment response (p = 0.05). Combination therapy was also significantly more effective than transcutaneous electrical nerve stimulation monotherapy regarding reduced number of wet days weekly (mean difference -2.28, CI -4.06 to -0.49), severity of incontinence (-3.11, CI -5.98 to -0.23) and daily voiding frequency (-2.82, CI -4.48 to -1.17). CONCLUSIONS: Transcutaneous electrical nerve stimulation in combination with oxybutynin for childhood urge incontinence was superior to monotherapy consisting of transcutaneous electrical nerve stimulation or oxybutynin, although the latter only reached borderline statistical significance. Furthermore, transcutaneous electrical nerve stimulation was associated with a decreased risk of oxybutynin induced post-void residual urine greater than 20 ml.

International Children's Continence Society's recommendations for therapeutic intervention in congenital neuropathic bladder and bowel dysfunction in children.

PURPOSE: We present a consensus view of members of the International Children's Continence Society on the therapeutic intervention in congenital neuropatic bladder and bowel dysfunction in children. MATERIAL AND METHODS: Discussions were held by a group of pediatric urologists and gastroenterologists appointed by the board. The following draft review document was open to all the ICCS members via the ICCS web site. Feedback was considered by the core authors and by agreement, amendments were made as necessary. The final document is not a systematic literature review. It includes relevant research when available as well as expert opinion on the current understanding of therapeutic intervention in congenital neuropatic bladder and bowel dysfunction in children. RESULTS: Guidelines on pharmalogical and surgical intervention are presented. First the multiple modalities for intervention that do not involve surgical reconstruction are summarized concerning pharmacological agents, medical devices, and neuromodulation. The non-surgical intervention is promoted before undertaking major surgery. Indicators for non-surgical treatments depend on issues related to intravesical pressure, upper urinary tract status, prevalence of urinary tract infections, and the degree of incontinence. The optimal age for treatment of incontinence is also addressed. This is followed by a survey of specific treatments such as anticholinergics, botulinum-A toxin, antibiotics, and catheters. Neuromodulation of the bladder via intravesical electrical stimulation, sacral nerve stimulation, transcutaneous stimulation, and biofeedback is scrutinized. Then follows surgical intervention, which should be tailored to each individual, based on careful consideration of urodynamic findings, medical history, age, and presence of other disability. Treatments mentioned are: urethral dilation, vesicostomy, bladder, augmentation, fascial sling, artificial urinary sphincters, and bladder neck reconstruction and are summarized with regards to success rates and complications. Finally, the treatment on neuropathic bowel dysfunction with rectal suppositories irrigation and transrectal stimulation are scrutinized.

Age related nocturnal urine volume and maximum voided volume in healthy children: reappraisal of International Children's Continence Society definitions.

PURPOSE: We determined normal, age related reference data regarding maximum voided volume and nocturnal urine production using the same methodology as in clinical practice. MATERIALS AND METHODS: A total of 62 girls and 86 boys without enuresis (mean +/- SD age 9.64 +/- 2.63 years, range 3 to 15) completed 4 days (2 weekends) of frequency-volume charts and 14 days of home recording of nocturnal urine production. From these recordings maximum voided volume with and without first morning void was derived for each subject. Also, average nocturnal urine volume with and without nocturia was calculated. Percentiles were produced by dividing the population into 1-year age groups. RESULTS: Based on 2,836 daytime voids and 1,977 overnight recordings, maximum voided volume and nocturnal urine volume showed a significant linear relationship with age but not with gender. Maximum voided volume with first morning void was significantly higher than without (403 +/- 137 ml vs 281 +/- 112 ml, p <0.0001) and the 50th percentile line of maximum voided volume with first morning void was 80 to 100 ml higher than Koff's formula (30 x [age + 1] ml). Conversely the 50th percentile of maximum voided volume without first morning void was almost identical to Koff's formula. Regarding nocturnal measurements, nocturia was noted on 128 nights (6.5%) and nocturnal urine volume on nights with nocturia was significantly higher than on nights without nocturia (365 +/- 160 ml vs 248 +/- 75 ml, respectively, p <0.0001). The 97.5th nocturnal urine volume percentile line of healthy children deviated markedly from the current International Children's Continence Society definition of nocturnal polyuria, especially at low and high ages. CONCLUSIONS: We demonstrate clearly that the universally used formula 30 x (age + 1) ml is indeed valid for a population of healthy Danish children but only if the first morning void is disregarded. Furthermore, we question the validity of the current International Children's Continence Society formula for nocturnal polyuria (nocturnal urine volume greater than 130% of maximum voided volume for age), and instead we propose the formula, nocturnal urine volume greater than 20 x (age + 9) ml.

Functional constipation in children.

PURPOSE: Constipation in children increases the likelihood of urinary incontinence, bladder overactivity, dyscoordinated voiding, a large capacity, poorly emptying bladder, recurrent urinary tract infection and deterioration of vesicoureteral reflux. We present a consensus related to the assessment, diagnosis and treatment of children with bowel dysfunction coexisting with a known disorder of urinary continence or voiding coordination. MATERIALS AND METHODS: A panel of international multidisciplinary clinicians working on pediatric continence care was invited to participate in the First International Children's Continence Society Bowel Dysfunction Workshop. The seminar sought to address the interrelationship of bowel dysfunction with disorders of urinary continence or voiding mechanics. RESULTS: Constipation is an end point defined by a constellation of symptoms, including infrequent passage of stool, difficulty passing stool, feces that are either large and hard or in small pieces, abdominal pain, palpable stool in the abdomen, stool in the rectal vault, loading on x-ray or fecal soiling. Assessment was done to identify potential organic causes of constipation, clarify symptoms, and identify altered motor behavior and abdomino/pelvic floor muscle incoordination. Whether the underlying problem was one of stool consistency, poor cognition, motivation or fear on the part of the child, or whether it related to gut motility, rectal sensation, stool retention or disordered emptying mechanics, the definitive therapy begins with rectal emptying of impacted stool followed by maintenance of regular soft stools to eliminate fear of pain with defecation. CONCLUSIONS: Constipation is a challenge to the clinician but with comprehensive assessment and systematic intervention children can achieve independent bowel emptying, which positively impacts bladder function.

Vitamin D insufficiency in Greenlanders on a westernized fare: ethnic differences in calcitropic hormones between Greenlanders and Danes.

We studied the influence of age, gender, latitude, season, diet and ethnicity on plasma 25-hydroxyvitamin D 25 OHD, PTH, 1,25-dihydroxyvitamin D, vitamin D-binding protein, bone-specific alkaline phosphatase, and osteocalcin levels in 46 Greenlanders living in Nuuk (64 degrees N) on a traditional fare (group A), 45 Greenlanders living in Nuuk on a westernized fare (group B), 54 Greenlanders (group C), and 43 Danes (Group D) living in Denmark (55 degrees N) on a westernized fare. Blood specimens were drawn both summer and winter. Vitamin D insufficiency (plasma 25 OHD <40 nmol/l) was common in all four study groups during summer (23-74%) and winter (42-81%). Compared to groups A and D, vitamin D insufficiency was significantly more frequent in groups B and C. In all groups, summer levels of 25 OHD were above winter levels. Multiple regression analysis revealed a significant effect of ethnicity. Compared to Danes, Greenlanders had higher 1,25-dihydroxyvitamin D levels, but lower 25 OHD and PTH levels despite relatively low plasma calcium concentrations. In addition to ethnicity, 25(OH)D levels were influenced by age, season (summer > winter), and diet (a traditional Inuit diet>westernized diet). Ethnic differences exist between Greenlanders and Danes. Our results suggest that Greenlanders may have an inherent lower "set-point" for calcium-regulated PTH release or an enhanced renal 1,25(OH)(2)D production. In addition to ethnicity, age, season, and diet were important determinants of vitamin D status. Changes from a traditional to a westernized fare are associated with a reduced vitamin D status in Greenlanders. Vitamin D supplementation should be considered.

Twenty-four-hour blood pressure among Greenlanders and Danes: relationship to diet and lifestyle.

BACKGROUND: Greenlanders have a lower rate of cardiovascular mortality and morbidity than Danes, possibly due to lower blood pressure. However, 24-h blood pressure has never been measured in Greenlanders. The aim of this study was to compare the 24-h blood pressure of Greenlanders and Danes, and to analyse the influence of Arctic food and lifestyle on blood pressure. METHODS: Four groups of healthy subjects were recruited for the study. Group I: Danes in Denmark consuming European food; group II: Greenlanders in Denmark consuming European food; group III: Greenlanders in Greenland consuming mainly European food; and group IV: Greenlanders in Greenland consuming mainly traditional Greenlandic food. All subjects underwent a physical examination, laboratory screening of blood and urine samples, and completed a questionnaire on diet, physical activity, smoking status, intake of alcohol, liquorices, vitamins and minerals. Twenty-four-hour blood pressure was measured. RESULTS: It was found that 24-h diastolic blood pressure was lower in Greenlanders than in Danes for the whole 24-h period and during both day and night-time, whereas systolic blood pressure was the same (mean 24-h blood pressure with 95% CI: Danes 123/75 mmHg (120/73-127/77), Greenlanders 122/ 69 (119/68-124/70)). Among Greenlanders, blood pressure increased with age and male gender, and systolic blood pressure increased with body mass index (BMI). No association with diet was found. The difference between the two populations persisted after controlling for age, gender, BMI, outdoor temperature, and lifestyle factors. CONCLUSION: Greenlanders have a lower 24-h diastolic blood pressure than Danes, and it is suggested that genetic factors are mainly responsible for the lower blood pressure level among Greenlanders.

A new mutation of the arginine vasopressin-neurophysin II gene in a family with autosomal dominant neurohypophyseal diabetes insipidus.

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomally dominant inherited disorder with a typical onset at one to six years of age. The genetic locus of FNDI is the arginine vasopressin-neurophysin II (AVP-NPII) gene. The gene encoding the precursor hormone (prepro-AVP-neurophysin II) is located in the chromosomal region 20p13 and contains three exons. Mutations that cause FNDI have been found to occur within the signal peptide of the prepro-AVP-neurophysin II precursor, within the coding sequence for neurophysin II and the vasopressin-coding sequence. A family (four members with FNDI, two without FNDI) in three consecutive generations was investigated. Index case was a now 22-year old man with a history of severe polyuria (18 L/day) and polydipsia first recognized at about 4-5 months of age. The arginine vasopressin-neurophysin II gene was investigated by direct sequencing of PCR products amplified from each exon. Subsequently, a restriction analysis was performed to verify the sequencing results. The affected individuals were found to have a missense mutation in exon 2 at nucleotide position 1887 (G to C) of the AVP-NPII gene. Using both restriction enzyme digestion and sequence analysis, the mutation was found in all affected family members, but not in the unaffected members studied. This mutation (1887 G to C) represents a novel mutation of the AVP-NPII gene.

Intra-individual variability in nighttime urine production and functional bladder capacity estimated by home recordings in patients with nocturnal enuresis.

PURPOSE: We evaluated the intra-individual variability and reproducibility of nighttime urine production on wet nights and functional bladder capacity estimated by long-term home recordings of monosymptomatic nocturnal enuresis. In particular, the intention was to evaluate the validity of 1 versus 2 weeks of recording when estimating urine volume on wet nights and 1 versus 2 weekends of recording when estimating functional bladder capacity. MATERIALS AND METHODS: We analyzed 120, 2-week home recordings of nighttime urine volume from patients with monosymptomatic nocturnal enuresis 6 to 16 years old (mean age 9.1) with at least 3 wet nights per week. Most patients were nonresponders or partial responders to desmopressin. Nighttime urine volume was estimated by weighing diapers before and after sleep, and measuring morning urine volume. Of the home recordings 62 included frequency volume charts for 2 weekends, which were evaluated for functional bladder capacity defined as the largest voided volume observed. RESULTS: No significant overall week-to-week differences were observed in average urine volume on wet nights and functional bladder capacity. There was a large intra-individual variability in all measured variables, which was most pronounced for functional bladder capacity and least pronounced for urine volume on wet nights. With regard to repeatability, the limits of agreement of urine volume on wet nights were -32% and 36% (95% confidence interval) as opposed to -54% and 48% for functional bladder capacity. CONCLUSIONS: In this study intra-individual week-to-week estimates of average urine volume on wet nights demonstrated acceptable variability and repeatability in contrast to functional bladder capacity. A reliable estimate of urine volume on wet nights could be obtained by 7 nights of home recording, whereas 4 days of daytime recording were necessary when estimating functional bladder capacity. Similar studies of patients who respond to desmopressin are needed.

A novel splicing mutation in the V2 vasopressin receptor.

In order to elucidate the molecular basis and the clinical characteristics of X-linked recessive nephrogenic diabetes insipidus (CNDI) in a kindred of Danish descent, we performed direct sequencing of the arginine vasopressin receptor 2 (AVPR2) gene in five members of the family, as well as clinical investigations comprising a fluid deprivation test and a 1-deamino-8-D-arginine-vasopressin (dDAVP) infusion test in the study subject and his mother. We found a highly unusual, novel, de novo 1447A-->C point mutation (gDNA), involving the invariable splice acceptor of the second intron of the gene in both the affected male (hemizygous) and his mother (heterozygous). This mutation is likely to cause aberrant splicing of the terminal intron of the gene, leading to a non-functional AVP receptor. The clinical studies were consistent with such a hypothesis, as the affected subject had a severe insensitivity to both the antidiuretic and the coagulation factors stimulatory actions of AVP and its analogue dDAVP. Direct sequencing of the AVPR2 is an accurate and rapid diagnostic tool for CNDI and early referral of patients for AVPR2 sequencing is therefore strongly suggested.

Clinical and molecular evidence of abnormal processing and trafficking of the vasopressin preprohormone in a large kindred with familial neurohypophyseal diabetes insipidus due to a signal peptide mutation.

The autosomal dominant form of familial neurohypophyseal diabetes insipidus (adFNDI) is a rare disease characterized by postnatal onset of polyuria and a deficient neurosecretion of the antidiuretic hormone, arginine vasopressin (AVP). Since 1991, adFNDI has been linked to 31 different mutations of the gene that codes for the vasopressin-neurophysin II (AVP-NPII) precursor. The aims of the present study were to relate the clinical phenotype to the specific genotype and to the molecular genetic effects of the most frequently reported adFNDI mutation located at the cleavage site of the signal peptide of AVP-NPII [Ala(-1)Thr]. Genetic analysis and clinical studies of AVP secretion, urinary AVP, and urine output were performed in 16 affected and 16 unaffected family members and 11 spouses of a Danish adFNDI kindred carrying the Ala(-1)Thr mutation. Mutant complementary DNA carrying the same mutation was expressed in a neurogenic cell line (Neuro2A), and the cellular effects were studied by Western blotting, immunocytochemistry, and AVP measurements. The clinical studies showed a severe progressive deficiency of plasma and urinary AVP that manifested during childhood. The expression studies demonstrated that the Ala(- 1)Thr mutant cells produced 8-fold less AVP than wild-type cells and accumulated excessive amounts of 23-kDa NPII protein corresponding to uncleaved prepro-AVP-NPII. Furthermore, a substantial portion of the intracellular AVP-NPII precursor appeared to be colocalized with an endoplasmic reticulum antigen (Grp78). These results provide independent confirmation that this Ala(-1)Thr mutation produces adFNDI by directing the production of a mutant preprohormone that accumulates in the endoplasmic reticulum, because it cannot be cleaved from the signal peptide and transported to neurosecretory vesicles for further processing and secretion.

Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus.

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder characterized by progressive postnatal deficiency of arginine vasopressin as a result of mutation in the gene that encodes the hormone. To determine the extent of mutations in the coding region that produce the phenotype, we studied members of 17 unrelated kindreds with the disorder. We sequenced all 3 exons of the gene by using a rapid, direct dye-terminator method and found the causative mutation in each kindred. In four kindreds, the mutations were each identical to mutations described in other affected families. In the other 13 kindreds each mutation was unique. There were two missense mutations that altered the cleavage region of the signal peptide, seven missense mutations in exon 2, which codes for the conserved portion of the protein, one nonsense mutation in exon 2, and three nonsense mutations in exon 3. These findings, together with the clinical features of FNDI, suggest that each of the mutations exerts an effect by directing the production of a pre-prohormone that cannot be folded, processed, or degraded properly and eventually destroys vasopressinergic neurons.

Differential relaxant responses to pinacidil of smooth muscle preparations contracted by a high concentration of potassium in isoosmolar and hyperosmolar solutions.

Contractions were produced in guinea-pig trachealis, aorta and pulmonary artery by depolarization with 124 mM K+ using two commonly applied techniques. Addition of KCl to the organ bath solution making it hyperosmolar induced slowly developing contractions, which were only weakly inhibited by pinacidil. Hyperosmolar mannitol-induced contractions showed similar characteristics. In contrast, contractions elicited by isoosmolar K+ Krebs solution developed more rapidly and could be completely suppressed by pinacidil (10(-6)-10(-3) M) in a concentration-dependent manner. The findings explain previously published discrepant results on the relaxant response to pinacidil of smooth muscle preparations contracted by high concentrations of K+, and indicate other mechanisms of action for pinacidil in addition to K+ channel opening, in the concentration range 10(-6)-10(-3) M.

Lack of effect of pinacidil on theophylline pharmacokinetics and metabolism in man.

Pinacidil, a pyridyl cyanoguanidine derivative, is a new antihypertensive vasodilator drug. It shares structural similarities with the histamine H2-receptor blocker cimetidine, an imidazole cyanoguanidine derivative, which is a potent inhibitor of cytochrome P-450 and of theophylline metabolism. In the present study the pharmacokinetics and metabolism of theophylline were determined in six healthy volunteers before and on the last day of oral pinacidil administration for two weeks. The dosage of pinacidil was 12.5 mg twice a day in the first week and 25 mg in the second. There were no significant changes in theophylline plasma clearance, terminal half-life or volume of distribution during pinacidil administration. Also the renal and metabolic clearance of theophylline and the formation clearances of the major theophylline metabolites in the urine (DMU, 1MU, 3MX) did not change significantly during administration of therapeutic doses of pinacidil.

Lack of effect of the vasodilator pinacidil on insulin secretion in healthy humans.

Pinacidil is a new antihypertensive vasodilator drug which is supposed to act by opening of ATP-sensitive and glibenclamide-sensitive K+ channels in vascular smooth muscle cell membranes. Similar K+ channels play an important role in insulin secretion from pancreatic islets cells. Inhibition of insulin secretion has been demonstrated with high concentrations of pinacidil in vitro. In the present study the insulin response to oral glucose were studied in six healthy subjects before and on the last day of 2 weeks treatment with pinacidil. The drug was given by the oral route 12.5 mg bid in the first week and 25 mg bid in the second. There were no significant changes in fasting blood levels of insulin or glucose, glucose-stimulated insulin secretion, or oral glucose tolerance during pinacidil administration. These results may suggest that pinacidil at therapeutic concentrations does not activate insulin regulating K+ channels in pancreatic islet cells.

Myocardial accumulation kinetics and pharmacodynamics in the isolated rabbit heart of a new inhibitor of dopamine reuptake, GBR 12909.

Myocardial accumulation of GBR 12909 showed monophasic exponential kinetics with a half-life of 93 min. The disposition followed a three-phasic exponential time-course with half-lives of 1.1, 17 and 98 min., respectively, which was interpreted as three-compartment kinetics. The drug accumulated 430 times in the myocardium at steady-state with 8, 30 and 61% of the drug amount referable to a central, superficial and two deeper myocardial drug pools. GBR 12909 produced concentration dependent (range 0.01 to 12400 nM) biphasic negative inotropic and chronotropic effects. The inhibitory Em-values with regard to contraction velocity were 42 and 105% with corresponding EC50-values of 29 and 688 nM and the related Hill-exponents were 0.6 and 1.1, respectively. Frequency and contraction amplitude related inhibitory Em-values were of similar size. Apparent dynamic steady states developed within about 17 min. Very marked monophasic negative dromotropic effects were observed with computer-derived inhibitory Em-values related to the electrocardiographic PQ- and QRS-intervals exceeding 100%. The frequency-corrected QTc-interval showed an initial increase of 10% but decreased to about 20% below control level at the highest two drug concentrations. Coronary flow-rate increased about 30% and then gradually decreased to near the control value. Oxygen consumption only decreased at the three highest concentrations. Our findings seem compatible with the view that GBR 12909 may possibly act in the myocardium as a membrane-stabilizer which causes inhibition of Na(+)- and Ca+(+)-influx over sarcolemma. Intracellular inhibition of Ca+(+)-liberation from organelles and other calcium depots also seems possible.

A comparison of the relaxant effects of pinacidil in guinea-pig trachea, aorta and pulmonary artery.

The relaxant activity of pinacidil, a proposed K+ channel opener, was compared in isolated guinea-pig trachea, aorta and pulmonary artery. In preparations precontracted by histamine or PGF2 alpha, pinacidil produced complete tracheal relaxation but only partial relaxation of vascular tissues. The order of responsiveness was: pulmonary artery greater than trachea greater than aorta. The slope of the pinacidil concentration-effect (C/E) curve was much steeper in the tracheal than in the vascular preparations. The pinacidil C/E curves for relaxation were similar when the three types of preparations were precontracted by 124 mM K+. Pretreatment with pinacidil caused a parallel shift of the tracheal histamine C/E curve to the right, whereas the maximal response to histamine was markedly depressed in the pulmonary artery.

Effects of pinacidil on guinea-pig airway smooth muscle contracted by asthma mediators.

Pinacidil is a new antihypertensive, direct vasodilator drug which has been classified as a K+ channel opener. The present study demonstrated a concentration-dependent relaxant activity of pinacidil in guinea-pig tracheal preparations. The potency and efficacy of pinacidil depended on the agent used to induce tracheal tone. Tracheal preparations with spontaneous tone or precontracted by different asthma mediators were completely relaxed by pinacidil. A high potency was found in spontaneously contracted preparations (EC50 = 7.8 x 10(-7) M). The EC50 values ranged from 2.3 to 5.4 x 10(-6) M in histamine-, PGF2 alpha- or LTC4-contracted preparations. When tone was induced by carbachol, the EC50 was 2.1 x 10(-5) M. In contrast, pinacidil produced incomplete relaxation and had a low potency in preparations contracted by 30 or 124 mM K+ Krebs solutions. This effect profile differed from that seen with beta 2-receptor agonists, xanthines and Ca2+ antagonists in guinea-pig trachealis and seems compatible with K+ channel opening as a primary mode of relaxation for pinacidil in airway smooth muscle.