Gonadotropin-releasing hormone immunization for the treatment of urethral sphincter mechanism incompetence in ovariectomized bitches

We have investigated GnRH immunization for the treatment of urethral sphincter mechanism incompetence in ovariectomized bitches. It has been reported that decreasing LH secretion through the use of GnRH agonists temporarily restores continence in some bitches. Therefore, decreasing the circulating LH concentrations by immunizing against GnRH might temporarily maintain continence in incontinent dogs. Sixteen incontinent dogs given phenylpropanolamine (PPA) to control incontinence were recruited for this study. Eleven dogs were immunized against GnRH (novel treatment group) at week 0, and nine dogs were vaccinated again 4 weeks later. Five dogs (standard treatment group) were vaccinated with a placebo twice at 4-week intervals. PPA was discontinued in the novel treatment group 2 weeks after revaccination, and standard-treatment dogs were given PPA for the duration of the study. Blood samples were collected before each treatment and at 6, 8, 10, 12, 16, 20, and 24 weeks and owners recorded episodes of incontinence throughout the study. Ten of the eleven dogs in the novel treatment group experienced side effects as a result of vaccination; two of these dogs experienced more severe side effects after the first vaccination and were withdrawn from the study as a result. Of the nine dogs that completed the vaccination series, four dogs remained continent after PPA was discontinued. For these four dogs, there was no difference in incontinent episodes when they were given PPA versus treatment with the vaccine. All nine novel-treatment dogs developed a GnRH antibody titer and experienced a significant decrease in circulating LH concentrations. In conclusion, GnRH immunization was effective in maintaining continence in four of the nine incontinent ovariectomized dogs, and in these dogs, treatment with the vaccine was comparable with treatment with PPA.     

The prevalence of urinary incontinence

Urinary incontinence is a significant health problem with considerable social and economic impact. It is important to distinguish between prevalence and incidence with regard to incontinence, and prevalence-the probability of having incontinence within a defined population at a defined point in time-is the more important when considering its impact and the utilization of healthcare resources. There are large variations in the severity and impact of incontinence, and its severity, frequency, and predictability all need to be considered when evaluating its effects on patients, The degree of bother is particularly significant when determining who will need treatment. Incontinence may be a result of bladder dysfunction, sphincter dysfunction, or a combination of both, but large-scale studies are not designed to determine the etiology. In young women, the prevalence of incontinence is usually low, but prevalence peaks around menopause, with a steady rise there-after into later life. Although the prevalence of stress and mixed (stress and urge) incontinence is higher than urge incontinence, the latter is more likely to require treatment. In women, moderate and severe bother have a prevalence ranging from about 3% to 17%. Severe incontinence has a low prevalence in young women, but rapidly increases at ages 70 through 80. In men, the prevalence of incontinence is much lower than in women, about 3% to 11% overall, with urge incontinence accounting for 40% to 80% of all male patients. Stress incontinence accounts for less than 10% of cases and is attributable to prostate surgery, trauma, or neurological injury. Incontinence in men also increases with age, but severe incontinence in 70- to 80-year-old men is about half of that in women. The most effective therapy for incontinence will rely on targeting the correct populations to be treated, which depends on how data is collected on prevalence and severity.     

The future of bladder control-intravesical drug delivery, a pinch of pepper, and gene therapy

The incidence of urinary incontinence and overactive bladder problems will continue to grow as the population ages. Future treatments are likely to include an implantable drug delivery system, gene therapy, and the intravesical use of the vallinoids capsaicin and resiniferatoxin (RTX). An understanding of the urothelium is essential for effective design of these therapies. Intravesical anticholinergic drug treatment is currently not widely used, but intravesical pumps are under development to provide less cumbersome treatment methods and will provide nonsurgical options for patients who cannot tolerate oral anticholinergic agents. Research on the use of capsaicin as an intravesicular drug has had limited success, but trials have confirmed the efficacy of intravesical capsaicin for detrusor hyperreflexia. RTX is as effective as capsaicin but without side effects, such as pain and inflammatory neuropeptide release. RTX treatment may eliminate the need for surgical and other drug treatments of lower urinary tract dysfunction in patients with spinal cord injuries. Gene therapy will change the practice of urology by addressing the deficiencies that cause symptoms rather than attacking the symptoms themselves.     

Concomitant medications and possible side effects of antimuscarinic agents

Antimuscarinic agents are the treatment of choice for overactive bladder syndrome; clinical experience and the literature support their efficacy, tolerability, and safety. The most common side effects experienced include dry mouth and constipation. Many commonly prescribed drugs have anticholinergic effects that could increase the anticholinergic "load" or "burden" in patients with overactive bladder, potentially increasing the frequency and severity of side effects. In addition, the adverse events associated with antimuscarinics may be more pronounced in the elderly, especially those taking multiple medications. Knowledge regarding the potential side effects associated with antimuscarinics is important so that patients can be advised and effectively treated.     

Effect of a long acting GnRH analogue or placebo on plasma LH/FSH, urethral pressure profiles and clinical signs of urinary incontinence due to Sphincter mechanism incompetence in bitches

In 23 bitches with urinary incontinence due to spaying, the effect of treatment with a long-acting formulation of leuprolide acetate on frequency of incontinence, plasma gonadotropin levels and urodynamic parameters was evaluated. In addition, the clinical effect was compared with that of treatment with alpha-adrenergics. Before treatment, the dogs' incontinent episodes occurred, on average, 4 times per day on up to 6 days per week. In the pre-trial after therapy with phenylpropanolamine (n=23) the episodes of incontinence decreased by 92%, in the double-blind study 5 weeks after GnRH-analogue (n=11) by 71%; and by 28% after the placebo (n=12). By the end of the study, nine of twenty-two leuprolide treated bitches responded completely to treatment and were continent for periods lasting 70-575 days after treatment. In another 10 dogs, response to therapy was partial and the frequency of incontinence was reduced by at least 50%. After therapy with placebo, one bitch had no episodes of incontinence for 412 days. Treatment with the GnRH-analogue significantly decreased the plasma gonadotropin levels but there was no correlation between the effect on gonadotropin levels and response to treatment. Treatment with leuprolide or placebo had no effect on urethral closure pressure regardless of the response to treatment. The hypothesis that the change of the plasma gonadotropin levels after spaying is the cause of reduced urethral closure function was not supported by the results of this study. A possible direct effect of GnRH-analogues on the bladder is discussed. Long acting GnRH analogues appear to be a well-tolerated alternative for urinary incontinence treatment, but they appear to be less effective than the alpha-adrenergics.     

Medical and minimally invasive treatment of urinary incontinence

Newer agents and procedures give urologists more options in treating patients who have urinary incontinence related to such etiologies as an ineffective sphincter, detrusor hypersensitivity, obstruction, or a combination of these. Abolition of the involuntary contractions characteristic of detrusor instability can be accomplished pharmacologically or surgically. First-line anticholinergic agents are tolterodine and oxybutynin XL, given orally. Alternatively, intravesical administration provides a high concentration of drug, such as capsaicin or resiniferatoxin, at the detrusor muscle level. However, this commits the patient to intermittent self-catheterization. Surgery is reserved for those who have failed prolonged trials of conservative therapies. For patients with intractable urge incontinence, urologists have the new technique of sacral nerve stimulation.     

Effect of transdermally administered hyoscine methobromide on nocturnal acid secretion in patients with duodenal ulcer.

Use of anticholinergic drugs in treatment of duodenal ulcers is limited by the side effects of widespread parasympathetic blockade evoked by usual therapeutic doses. A study was conducted into the effectiveness of transdermal delivery of hyoscine methobromide using a new system which releases the drug into the circulation at a controlled rate. In six patients whose duodenal ulcer had healed secretion of acid was measured over two nights, the first on placebo and the second on hyoscine methobromide. All patients responded to the active drug and showed a significant inhibition of acid secretion. Four subjects complained of a dry mouth after overnight treatment with hyoscine methobromide; no other side effects were reported. Transdermal delivery of anticholinergic drugs may be useful in maintenance treatment of duodenal ulcers and further clinical tests are indicated.     

Is There a Role for alpha-Blockers for the Treatment of Voiding Dysfunction Unrelated to Benign Prostatic Hyperplasia?

alpha-Adrenoreceptor antagonists have become the primary medical treatment for lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). It was presumed that the primary mechanism by which alpha-blockers reduced lower urinary tract symptoms (LUTS) was by relaxation of smooth muscle in the prostate through a sympathetic response. Reduction of outlet resistance leads to changes in bladder function, thus improving both storage and voiding symptoms. However, it was observed that many patients with BPH-associated LUTS had significant improvement in storage symptoms without subjective or objective improvement in voiding. Storage symptoms associated with detrusor overactivity (frequency, urgency, and urge incontinence) are typically thought of as being parasympathetically mediated, and therefore anticholinergic medications have been the mainstay of pharmacological treatment, but recent work has suggested that several nonparasympathetic-mediated mechanisms may cause detrusor overactivity. Because alpha receptors appear to play a role in lower urinary tract function at multiple sites and levels, alpha-blockers could be used to treat voiding dysfunction not related to BPH. In addition, these nonprostate effects should be gender-independent, making the use of alpha-blockers plausible in women with specific types of voiding dysfunction.     

Numerous topics covered as presidents and CEOs meet at CMA

We conducted a 1-day survey to determine the prevalence of urinary incontinence among patients in four home care programs in southern Ontario and the characteristics of incontinent patients. Of the 2801 patients for whom the continence status was known, 22% were assessed as incontinent. The mean age of the incontinent patients was 74 (extremes 18 and 101) years, and 65% were women. A total of 89% had at least one functional disability in cognition, mobility, transferring in and out of bed or chair, or undoing garments. The incontinence was moderate to severe in 41% of the patients, and 95% of the family caregivers living with these patients viewed the incontinence as a problem. Palliative rather than remedial treatment was used most frequently; only 5% of the patients had undergone a urodynamic assessment in the previous year. Future research should emphasize the assessment of remedial interventions.     

Changing attitudes in the management of urinary incontinence-the need for specialist nursing.

Much interest has been shown recently in the plight of the incontinent patient and how incontinence should be managed. Incontinence has a complex aetiology and may be part of many medical and social problems. Because there is a delay between completing investigations and making a diagnosis we have established a system of nursing care. Initially this was meant to provide the person protective garments and appliances, but it now covers management in both the community and the hospital. The preliminary results show that patient assessment is effective and that specialist nurses and a co-ordinated scheme to educate both doctors and nurses are needed.     

New frontiers in the treatment of overactive bladder and incontinence

In this article the author tries to forecast how urologists will treat the overactive bladder (OAB) in the next decade. He reviews drugs currently under development and also logical and exciting pharmacological targets that would be suitable targets for treating OAB in the future. The author also discusses intravesical therapy and alternative drug delivery methods, such as intravesical capsaicin and botulinum toxin. There are many advantages to advanced drug delivery systems, including the achievement of long-term therapeutic efficacy, decreased incidence and severity of side effects, and improved patient compliance. Special emphasis is placed on approaches to modulating bladder afferent nerve function to prevent OAB. Speculation on future techniques such as gene therapy can also be considered for treating OAB, because they may make it possible to access all of the genitourinary organs via minimally invasive techniques. Traditional anticholinergic therapies are limited in their effectiveness. There is great hope for future research and therapy for OAB and urinary incontinence.     

Pathophysiology of overactive bladder and urge urinary incontinence

Storage symptoms such as urgency, frequency, and nocturia, with or without urge incontinence, are characterized as overactive bladder (OAB). OAB can lead to urge incontinence. Disturbances in nerves, smooth muscle, and urothelium can cause this condition. In some respects the division between peripheral and central causes of OAB is artificial, but it remains a useful paradigm for appreciating the interactions between different tissues. Models have been developed to mimic the OAB associated with bladder instability, lower urinary tract obstruction, neuropathic disorders, diabetes, and interstitial cystitis. These models share the common features of increased connectivity and excitability of both detrusor smooth muscle and nerves. Increased excitability and connectivity of nerves involved in micturition rely on growth factors that orchestrate neural plasticity. Neurotransmitters, prostaglandins, and growth factors, such as nerve growth factor, provide mechanisms for bidirectional communication between muscle or urothelium and nerve, leading to OAB with or without urge incontinence.     

髁突-翼外肌解剖复位与游离复位治疗髁状突骨折的疗效比较

目的:比较髁突-翼外肌解剖复位与游离复位治疗髁状突骨折的疗效,促进髁突形态恢复。方法:收治的80例单侧髁状突骨折患者随机分为两组,每组40例,A组行髁突-翼外肌解剖复位术,B组行髁状突游离复位术,术后3个月、6个月观察髁突形态及下颌骨运动功能变化。结果:A组治愈率为90%,高于B组的70.00%(P0.05);术后3个月A组髁状突吸收、张口受限、开口偏斜、咬合关系紊乱、关节弹响发生率分别为12.50%、15.00%、15.00%、7.50%、12.50%,均低于B组的32.50%、35.00%、37.50%、25.00%、35.00%(P0.05);术后6个月A组张口受限、关节弹响发生率为5.00%、2.50%,均低于B组的20.00%、20.00%(P0.05);两组术后并发症发生率比较差异无统计学意义(P0.05)。结论:髁突-翼外肌解剖复位术保留髁状突骨折患者骨折断端血运,髁突形态及下颌骨运动能力恢复良好,疗效优于髁状突游离复位术。     

The role of the primary care physician in the management of bladder dysfunction

Urinary incontinence is a major health challenge for primary care physicians. Unfortunately, the majority of incontinent patients remain untreated. Primary care physicians are ideally positioned to screen for and manage urinary incontinence. A knowledge of basic micturition physiology is important for the physician to accurately identify the cause of incontinence and arrive at the correct treatment course. To this end, this article reviews the physiology of the lower urinary tract, describes the clinical types of urinary incontinence, and outlines a stepwise approach for the primary care physician to the basic evaluation and management of patients with this condition.     

Synthesis and potassium channel opening activity of substituted 10H-benzo[4,5]furo[3,2-b]indole-and 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids

Compounds in a structurally novel series of substituted 10H-benzo[4,5]furo[3,2-b]indole-1-carboxylic acids and related 5,10-dihydro-indeno[1,2-b]indole-1-carboxylic acids were prepared and shown to possess potent, bladder-selective smooth muscle relaxant properties and thus are potentially useful for the treatment of urge urinary incontinence. Electrophysiological studies using rat detrusor myocytes have demonstrated that prototype compound 7 produces a significant increase in hyperpolarizing current, which is iberiotoxin (IbTx)-reversed, thus consistent with activation of the large-conductance Ca(2+)-activated potassium channel (BK(Ca)).     

Prevalence of urinary incontinence.

The prevalence of urinary incontinence was investigated by determining the number of incontinent patients under the care of various health and social service agencies in two London boroughs and by a postal survey of the 22 430 people aged 5 years and over on the practice lists of 12 general practitioners in different parts of the country. The prevalence of incontinence known to the health and social service agencies was 0.2% in women and 0.1% in men aged 15-64 and 2.5% in women and 1.3% in men aged 65 and over. The postal survey, to which 89% of the people whose correct address was known replied, showed a prevalence of urinary incontinence of 8.5% in women and 1.6% in men aged 15-64 and 11.6% in women and 6.9% in men aged 65 and over. Nulliparous women had a lower prevalence than those who had had one, two, or three babies, but within the parity range of one to three there were no differences in prevalence. The prevalence was appreciably increased in women who had had four or more babies. Incontinence was moderate or severe in a fifth of those who reported it in the postal survey, of whom less than a third were receiving health or social services for the condition. Incontinence is a common symptom, and many unrecognised cases appear to exist. There may be considerable scope for improving its management.     

Worms and malaria: blind men feeling the elephant?

For thousands of years the deadliest human parasite, Plasmodium falciparum, has been evolving in populations also infected by the most prevalent parasites, worms. This is likely to have shaped the genome of all 3 protagonists--man, worms and malaria. Observational studies in Thailand have shown that although P. falciparum malaria incidence increased two-fold in helminth-infected patients, there was a 64% reduction of cerebral malaria and an 84% reduction of acute renal failure in helminth-infected patients relative to those without helminths. In addition, it was suggested that mixed infections, anaemia and gametocyte carriage were more frequent in helminth-infected patients. On the contrary, fever was lower in helminth-infected patients. The present hypotheses, their implications and the limitations of the results described and of those from studies in Africa are discussed.     

Pre-clinical and clinical pharmacology of selective muscarinic M3 receptor antagonists

Muscarinic M3 receptor antagonists have therapeutic potential for the treatment of disorders associated with altered smooth muscle contractility or tone. These include irritable bowel syndrome (IBS), chronic obstructive airways disease (COAD) and urinary incontinence. Zamifenacin is a potent muscarinic receptor antagonist on the guinea pig ileum (pA2 value 9.27) with selectivity over M2 receptors in the atria (135-fold) and M1/M4 receptors in the rabbit vas deferens (78-fold). In addition, zamifenacin had lower affinity for the M3 receptor in the salivary gland (pKi 7.97). In animals, zamifenacin potently inhibited gut motility in the absence of cardiovascular effects and with selectivity over inhibition of salivary secretion. In healthy volunteers, zamifenacin inhibited small and large bowel motility and increased the rate of gastric emptying over a dose range which was associated with minimal anticholinergic side effects. These data show that zamifenacin, a selective muscarinic M3 receptor antagonist, was well tolerated in man and was efficacious as an inhibitor of gut motility. Further studies in patients are required with muscarinic M3 receptor antagonists to confirm efficacy against symptoms in diseases associated with altered smooth muscle contractility.     

Behavioural treatment of urinary incontinence in geriatric patients.

Urinary incontinence and a program to treat it were studied in a geriatric hospital. Of 161 men, 58 (36%) were incontinent. The most common probable causes were cerebrovascular accident and organic brain syndrome. Evaluation by cystometry (after treatment of infections) in 30 patients showed 24 (80%) to have detrusor hyperreflexia. Twenty patients with hyperreflexia completed a timed-voiding routine, which benefited 17 of them (85%).     

网片重建治疗盆腔器官脱垂的临床疗效及安全性评价

目的:探讨经阴道放置网片的全盆底重建术治疗重度子宫脱垂的临床疗效和安全性。方法:选择2010年7月至2015年6月在青岛大学附属医院因重度盆腔器官脱垂接受全盆底重建术的患者126例,回顾性分析患者的临床资料、生活质量评分及并发症等相关资料。结果:126例患者平均手术时间(67.18±18.00)min,出血量(56.27±26.47)m L,留置尿管(3.47±0.94)天,住院天数(4.21±0.93)天。术后尿潴留的发生率为3.96%、阴道壁血肿0.79%、术后肢体疼痛7.14%、下肢静脉血栓0.79%,所有患者术中均无膀胱或直肠损伤等严重并发症的发生。126例患者中,111例完成随访(88.09%,111/126),随访时间为6~48个月,中位随访时间为27个月。术后发生网片暴露1例(0.9%,1/111),网片挛缩1例(0.9%,1/111),慢性盆腔疼痛2例(1.80%,2/111)、新发尿失禁6例(5.4%,6/111)。其中3例为急迫性尿失禁(2.7%,3/111),3例压力性尿失禁(2.7%,3/111)。盆底重建术后共有3例患者出现复发,其中2例因症状明显再次行手术治疗,客观治愈率的为97.29%(108/111),主观治愈率为98.19%(109/111)。与术前相比,术后6个月、12个月生活质量评分(PFDI-20)均较前均明显降低(P0.05)。术后21例患者恢复性生活,性生活疼痛者3例(14.28%),性生活不适者4例(19.04%),总体性生活满意度为85.71%(18/21)。结论:全盆重建术治疗重度盆腔器官脱垂的疗效较好,且网片相关并发症的发生率较低。