Micturition disorder is a term which collectively refers to micturition-related pathological conditions, encompassing dysuria, pollakiuria, miction pain, and urinary incontinence.
Dysuria generally refers to a state where smooth urination is disturbed. Typical symptoms include: delay between the desire to void and the initiation of micturition; thin stream of urine, time for voiding prolonged; post-micturition dribble; conscious exertion of abdominal pressure needed to initiate voiding; and sense of residual urine remaining in the bladder immediately after urination. A special form of dysuria is urinary retention, which refers to a state in which voluntary micturition is disturbed and is characterized by retention of urine. Causes of urinary retention are broadly divided into (1) those attributed to neurological factors, including incoordination of the bladder smooth muscle and detrusor-sphincter dyssynergia, and (2) those attributed to organic factors, such as prostate-associated diseases, bladder neck sclerosis, and urethral stricture. Until today, however, the causes have not yet clearly elucidated and current theory holds that neurological changes and organic changes are closely related to each other. Thus, in order to formulate a remedy, studies should be directed not only at localized anatomy, but at the entire urinary system, including the bladder, the prostate, and the external sphincter (see Medicine Journal, vol. 33, S-1, 193-197 (1997).
Pollakiuria refers to a pathological condition in which frequency of urination rises to an abnormally high level. Frequency varies greatly from day to day among healthy individuals, and therefore, it is difficult to demarcate clearly. However, as a rough yardstick, frequency of more than ten times during the day and more than 2 times at during sleeping hours is regarded to be pollakiuria. Pollakiuria is sometimes accompanied by miction pain.
Miction pain is a pain felt along the urethra during micturition. Patients may experience this pain only at the initial or the final stage of voiding.
Urinary incontinence refers to a pathological condition where there is an involuntary letting of urine. There are several types of urinary incontinence: overflow incontinence where although the bladder is filled with urine normal micturition is inhibited and urine eventually overflows when a condition of urinary retention is reached; urge incontinence in which patients cannot suppress voiding once they have the desire to micturate; stress incontinence where incontinence occurs only when abdominal pressure is elevated; and true incontinence in which the bladder can no longer hold urine due to, for example, a dysfunction of the urethral sphincter. Urinary incontinence is often accompanied by pollakiuria.
Causes of micturition disorders include (1) disturbance of the nerves which control the bladder/urethral sphincter, which is attributed to, for example, spinal injuries, cerebrospinal tumors, cerebrospinal vascular disorders, myelitis, multiple sclerosis, Parkinson's disease, spinal meningoceles, radical surgery for uterine cancer, and radical surgery for colon cancer; (2) stimulation of the bladder membrane due to lesions in the bladder wall or inflammation or fibrosis of the muscle layers of the bladder, caused by cystitis, prostatitis, calculus at the lower end of the ureter, bladder cancer, etc. (3) injuries of the urethral sphincter; (4) obstructive lesions in the urethra attributed to prostatic hypertrophy. prostatic cancer, bladder neck sclerosis, or urethral stricture. Therapies for micturition disorders focus firstly on the treatment of underlying disorders/diseases. However, when such treatment is impossible, symptomatic treatment is usually attempted.
Among the above-mentioned causal disorders/diseases, diseases of the lower urinary tract system, such as lesions in the bladder wall or urethral obstructive lesions, such as cystitis, prostatitis, prostatic hypertrophy, bladder neck sclerosis, obstructive lesions, are intractable, and therefore there is a strong need for the development of effective pharmaceuticals.
Cystitis refers to infectious or non-infectious inflammation which primarily arises in the bladder membrane and submucosal tissue. In some cases, cystitis invades muscle layers. Generally, cystitis is divided into acute and chronic forms on the basis of clinical progress. Depending on the presence or absence of obstructive diseases in the lower urinary tract, cystitis is further classified into simple cystitis and complex cystitis. Generally, simple cystitis proceeds acutely and responds well to antimicrobial drugs. In contrast, complex cystitis proceeds chronically and often does not respond well to antimicrobial drugs, and is thus sometimes referred to as intractable cystitis. Intractable cystitis includes interstitial cystitis, hemorrhagic cystitis, bacterial intractable cystitis, and eosinocytic cytitis (see Medicine Journal, vol. 31, No. 3, 81-84 (1995)).
Interstitial cystitis is a disease of the bladder in which the present complaints (PC) include pain in the lower abdomen due to repletion of the bladder (bladder pain), pollakiuria, urinary urgency, or dysuria. These can be accompanied by complaints of a mental nature, including sensations of incomplete urination, malaise, depression, and anxiety, but are not accompanied by infection or peculiar pathological findings. In 1987, the National Institutes of Health (USA) provided guidelines--although thought to be incomplete--or diagnosing interstitial cystitis. According to the guidelines, causes of this disease, which have not been completely elucidated, include disturbance of the lymphatic system; chronic infection; disturbance of the nervous system; mental disorder; autoimmune disease; angiitis; toxic factors in the urine; compromised bladder defensemechanisms; and mast cells (Clinical Urology, Vol. 52, No. 9, 635-640, August, 1998). In the United States, about 500,000 patients currently suffer from interstitial cystitis and the American Urological Association includes in each of its conferences special sessions presenting the results of research into interstitial cystitis. The prevalence of interstitial cystitis is higher in women. Such female patients have difficulty in working and not infrequently become targets for firing and are subjected to sexual harassment. In Japan also, there may be many victims of interstitial cystitis. However, significant numbers of undiagnosed victims may be hidden among patients who complain of pollakiuria, in view that universal standards for diagnosis have not yet been established.
Current therapy for interstitial cystitis includes hydrodistention therapy; and drug therapy by use of drugs such as antidepressants, anti-histaminic agents, steroids, dimethyl sulfoxide (DMSO), and heparin. In hydrodistention therapy, the bladder is expanded through hydraulic pressure, and abatement is observed in approximately 50-60% of cases. However, after completion of the therapy, the condition may become aggravated in 2-3 weeks or may recur in 4-12 months. In such cases, the therapy must be repeated. Antidepressants elevate the patient's pain threshold and induce sleep. However, such drugs do not treat the underlying pollakiuria. Anti-histaminic agents have been used because it is believed that the development of interstitial cystitis is related to mast cells. However, it is accepted that these agents used alone rarely control the condition and must be used in combination with other therapies. Steroids, which are used for a comparatively large number of patients in Japan, are not drugs of first choice in Europe and the United States. This is because the optimum dose and administration duration of steroids have not been fully determined and their effects are unpredictable. DMSO is said to be effective for suppressing inflammation. It is reported that injection of DMSO into the bladder is effective in about 30-40% of cases and remission of the condition lasting for 5-6 years is observed (J. Urol., 98, 671 (1986)). However, there are some cases of resistance to this therapy, and in such cases a subsequent treatment must be considered. In addition, results of animal tests indicate that DMSO may be in implicated in cataract formation although no such results have been reported in humans. Therefore, DMSO must be used with caution. Heparin is reported to be effective in about 50t of cases when used as intrabladder injection therapy (Br. J. Urol., 73, 504-507 (1994)). However, this method is not readily acceptable as patients must be taught to self-catheterize to provide a route for injecting heparin into the bladder.
Hemorrhagic cystitis, another type of cystitis, is characterized primarily by the presence of heavy haematuria. It can be caused in a number of different ways. Main causes are 1) viruses such as adenovirus and influenz a virus, 2) microorganisms including bacteria such as Escherichia coli, Proteus, and Pseudomonas aeruginosa, 3) physical and chemical stimulation by radiation exposure or by the administration of drugs (cyclophosphamide, hexamine mandelate, methicillin, etc.). Previously, hemorrhagic cystitis was sometimes considered an allergic response. However, proving that a certain case of hemorrhagic cystitis is indeed an allergic response is not necessarily easy, and moreover, the frequency of cases that can be a ttributed to an allergic response remains unclear.
A typical example of bacterial intractable cystitis is bladder tuberculosis. Bladder tuberculosis exhibits clear symptoms of cystitis and pyuria, and conventional antibacterial agents are not effective remedies.
Eosinophilic cystitis exhibits symptoms similar to those of acute bacterial cystitis and pyuria, with urine culture testing negative. Antibacterial agents have no effect on eosinophilic cystitis. This pathological condition is caused by an allergic reaction against drugs having antiallergic properties. Typical examples of such drugs include Tranilast, but other antiallergic drugs may also induce cystitis. Pathologically, eosinophilic cystitis is characterized by dominant chronic inflammatory findings with no characteristic trait. Eosinophilic cystitis may be easily alleviated by withdrawing the drugs which induced the condition. However, when the condition is difficult to alleviate, administration of steroids, and ultimately cystectomy, must be performed.
Prostatitis is roughly categorized into acute prostatitis and chronic prostatitis.
The majority of acute prostatitis cases are caused by bacterial infection, with urinary tract infection via the urethra being the most common. Hematogenous infection or infection from surrounding organs are minor causes. Typical examples of inflammation-inducing bacteria include Gram-negative bacteria (particularly Escherichia Coli) and Gram-positive bacteria (staphylococcus). Histologically, edema, expansion, inflammatory cells infiltration, necrosis of intestinal epithelium, and formation of small abscesses are observed in a part or all of the prostate. In some cases, small abscesses may be fused to form large abscesses, invading and infiltrating surrounding organs. The symptoms of acute prostatitis include systemic symptoms such as chills, trepidation, and high fever, which induce an increase in peripheral leukocytes. Examples of localized symptoms of the condition include miction pain, pollakiuria, dysuria, and pain or unpleasant sensations in the perineal region. Concomitant swelling of the prostate may induce urinary retention.
Chronic prostatitis is classified into two types, which are, firstly, a condition where acute prostatitis becomes chronic and, secondly, where it proceeds as chronic prostatitis from its onset. Histologically, inflammatory infiltrate and hyperplasia of the connective tissue are observed, as well as constriction and obstruction of the lumen. When the condition lasts for a prolonged period of time, degeneration of the epithelium along with considerable fibrosis is observed. Few systemic symptoms are apparent, but the condition induces various local symptoms such as dysuria, pollakiuria, miction pain, unpleasant sensations after urination, pain, compressive sensations or generalized unpleasant sensations in the genitalia.
Prostatic hypertrophy refers to a pathological condition in which hypofunction of the prostate due to aging induces formation of fibromuscular or glandular nodules on glands surrounding the urethra. These nodules gradually enlarge, resulting in an overall enlargement of the prostate. Prostatic hypertrophy itself is a benign disease, but when the disease proceeds and the prostate expands, the disease causes obstruction of the urinary tract, which results in micturition disorders and renal dysfunction. Hitherto, many theories explaining the causes of prostatic hypertrophy have been proposed. Since the prostate is a sex-hormone-dependent organ, many studies have been carried out from this viewpoint. However, the details of the disease have not yet been elucidated.
The bladder neck is the portion ranging from the internal urethral opening to the starting point of the posterior urethra. Bladder neck sclerosis is a pathological condition in which the walls of this section become thick and hardened, thereby losing elasticity and constricting the lumen, resulting in micturition disorders. Pathological profiles include hypertrophy of smooth muscle bundles and growth of collagen fiber around the bladder neck, and in many cases, due to complications caused by inflammation, submucosal edemas and infiltration of inflammatory cells are observed. A variety of theories explaining the causes have been proposed, including aging; progress of sclerosis accelerated by inflammation of the prostate, posterior urethra, bladder neck, etc.; and the possible relation to prostate atrophy. Cases of secondary bladder neck sclerosis include those manifesting complications associated with neurogenic bladder, conditions which follow chronic inflammatory changes (in particular tuberculosis), and those caused by the invasion of malignant tumors such as prostate cancer. Currently, radical therapy is considered difficult.