Background art While any infectious condition of the urinary bladder will be associated with inflammatory changes and a concomitant hypersensitization of the bladder mucosa and/or underlying musculature, it is the progressive and ultimately chronic manifestations of the primary clinical condition that results in the irritative voiding symptoms and supra-pubic pain associated with bladder filling. Aside from the overt clinical symptoms evidenced during chronic cystitis, histological changes in the mucosal lining of the bladder, as well as underlying tissue, may undergo keratinising metaplastic changes which, although non-malignant, may progress to conditions of patent malignancy unless resolved or controlled.

Long term or chronic indwelling catheterisation of quadriplegic or paraplegic patients may result in chronic or recurrent urogenital microbial infections of a primarily ascending nature. It is well established that biofilm proliferation in indwelling catheters serves as the primary focus of recurrent infection, and sub-optimal anti-microbial therapy may lead to progressive resistance to the previously efficacious therapeutic agents. Protracted microbial infections of the bladder lumen give rise to concurrent inflammatory changes in the superficial mucosal layer and thereafter also in the deeper underlying tissues and musculature.

In advanced cases, chronic changes of the bladder architecture may result in patent symptoms of cystitis without any microbial agent being present and the focus of the inflammatory changes has been adjudged to be interstitial in nature. These chronic, recurrent bouts of interstitial inflammation of the urinary bladder wall and its surrounding tissue constitute a substantially hyperaesthetic and debilitating disease. The condition has been shown to be primarily associated with women, although up to 10% of cases may manifest in men.

Patients diagnosed with interstitial cystitis are limited by the variety and value of medical and surgical interventions available for the resolution of symptoms. Treatment may vary from rudimentary pH modulation, i. e. urinary acidifiers to alter the internal environment suited to the bacterial populations present both in and on the bladder mucosa, through to rigorous antimicrobial therapy where the specific antimicrobial has been typed to ensure optimal efficacy against the offending microbial populations. Similarly, antimicrobials are selected on the basis of their specific path of urinary excretion, thus ensuring optimal concentrations of antimicrobial agents in close proximity to the sources of infection.

In cases of protracted microbial infection, with a scenario of potential antimicrobial resistance developed by the microbe populations, these infections of the transitional epithelium of the bladder mucosa and the underlying musculature, may give rise to non- specific inflammatory immunogenic conditions of the tissue. These conditions may progress to full-blown symptoms of cystitis without an infectious microbial component and have been described as being akin to a hypersensitivity reaction by the body against its own tissue types.

In cases of patients receiving radiation therapy, whether generalised or specific to the pelvic region, a frequent sequel to the intervention is that of haemorrhagic cystitis, the duration and severity of which is directly dependent on the magnitude and frequency of the radiation treatment. Repeated and long-term radiation treatments have been shown to be associated with mucosal ulceration as well as telangiectatic changes of the vasculature of the bladder wall and the overt haematuria is a direct consequence of these changes.

Object of the invention It is accordingly an object of this invention to provide a more effective method for the treatment of chronic, recurrent infectious and non-specific inflammatory conditions of the urinary bladder and associated anatomical architecture that will overcome or at least minimise the above problems.

Disclosure of the invention According to the invention there is provided a method of treating both acute and chronic infectious cystitis, the method including the steps of electrochemically activating a dilute aqueous solution such that the electrochemically activated, aqueous solution includes separable and both of an aqueous, mixed oxidant, predominantly anion-containing solution and an aqueous, mixed reductant, predominantly cation-containing solution; separating the aqueous, mixed oxidant, predominantly anion-containing solution from the aqueous, mixed reductant, predominantly cation-containing solution ; infusing or instiling the aqueous, mixed oxidant, predominantly anion-containing solution into lumen of a urinary bladder ; and through a process of hydrodistention optimising contact between the infused or instiled aqueous, mixed oxidant, predominantly anion-

containing solution and the entire bladder mucosal surface so as to ensure maximal contact between infectious microbial agents and the solution.

The electrochemically activated, aqueous solution may be selected from a group consisting of an anion-containing solution ; a cation-containing solution; a mixture of an anion-containing solution and a cation-containing solution ; an anion-containing solution having been prepared from an anion-containing solution, a cation-containing solution or a mixture of an anion-containing solution and a cation-containing solution ; and a cation- containing solution having been prepared from an anion-containing solution, a cation- containing solution or a mixture of an anion-containing solution and a cation-containing solution.

The predominantly anion-containing solution is referred to hereinafter for brevity as the "anolyte solution"or"anolyte", and the predominantly cation-containing solution is referred to as the"catholyte solution"or"catholyte".

The electrochemically activated, aqueous solution may be prepared by means of electrolysis of an aqueous solution of a salt. The salt may be selected from the group consisting of alkali and alkali earth metal chlorides ; -carbonates;-bi-carbonates ; - phosphates ;-sulphates, or-nitrates; for example, sodium chloride ; non-iodated sodium chloride ; potassium chloride ; calcium chloride ; sodium carbonate;-bicarbonate ; and- phosphate; potassium carbonate;-bicarbonate ; and-phosphate; calcium phosphate; sodium- ;-potassium ; and calcium nitrate; and a mixture of at least two of the aforementioned salts.

The electrochemically activated, aqueous solution may be produced from a relatively low concentration aqueous salt solution. Depending on the particular process being performed, and the method for producing the electrochemically activated solution (e. g. with or without pre-dilution of the feed solutions), the aqueous salt solution concentration may be between 0. 0001% to 10%, and for some specific systems without pre-dilution of the feed, preferably between about 0.3% and 0.5% aqueous salt solution.

The anolyte and the catholyte may be produced by an electrochemical reactor or so- called electrolysis device, having a through flow electro-chemical cell with two c-axial cylindrical electrodes, with a tubular ceramic diaphragm located co-axially between the two electrodes so as to separate an annular inter-electrode space into a co-axial, annular catholytic and an annular anolytic chamber arrangement. The electrochemical cell may have predetermined design and geometrical relationships, ensuring optimum fluid flow and re-circulation patterns. The cell may have a relatively small, annular, cross-sectional total open area for fluid flow, preferably of about 180mm2, thus causing turbulent fluid flow there through so as to ensure maximum exposure of the solutions to the electric field.

The anolyte and the catholyte may be produced in the electrochemical cell under predetermined operational parameters, including a relatively low current, preferably of about 5A to 8A, and a relatively high voltage, preferably of about 6V to 48V, and more preferably between 8V and 24V, thus providing a relatively high voltage gradient or electric field intensity at the interface between the electrode surface and electrolyte, estimated to be about 1 o6 V/cm.

The salt solution may be electrolysed to produce the anolyte and the catholyte with mixed oxidant and mixed reductant species. These species may be labile and after about 96 hours, the concentration and activity of the various activated species may reduce substantially with relatively little, alternatively no active residue remaining.

The anolyte solution may have a redox potential of about between +300mV and +1200mV. The anolyte solution may have a pH of between 2 and 8, and preferably a pH of 7. Depending on the salt (s) in the feed stream used in the activation process, the anolyte solution may include mixed oxidant species such as CIO ; CIO-; HCIO ; OH-; HO2- ; H202 ; Os ; S208 and C1206 The catholyte solution generally may have a pH of between 7 and 13, and preferably a pH of about 11.5, and a redox potential of between-200 mV and-1100mV and preferably of about-800mV. Depending on the salt (s) in the feed stream, the catholyte solution may include mixed reductant species such as OH- ; Hs' ; 02 ; H2 ; HO2# ; H02-and 02.

Depending on the source of the water and the salt used, anolyte may contain organic radicals and other components such as Cl2, HCIO, CIO, CIO, Cl, HO2, HO2, O2, HO, <BR> <BR> <BR> <BR> <BR> O3, O2#, 3O2, FO2, O#, H3O+, Cl#, H#, H2O2, Cl2O, ClO2#, HCl, Cl2O7, S2O82-, C2O62-, HClO, H2SO4, and HSO3C1. Catholyte may contain HO', H302, °2'HO2, H202, H2, HO, H2-, NaOH, KOH, Ca (OH) 2 and Mg (OH) 2. Analysis of the inorganic components of these solutions has shown varying quantities of aluminium, calcium, magnesium, manganese, potassium, sodium, molybdenum, ammonium, orthophosphate, silica and chloride.

The varying levels of saline concentration and the mineral content of the feed water, as well as the operational variables of the electrochemical reactor, preferably the different flow rates, flow regimes, -paths and-rates of recycle, currents and potential differences, may be adjustable so as to produce anolyte and catholyte with suitable physical and chemical characteristics, with specific conductivity, redox potential and pH, concentration of"activated species"and other characteristics, for particular applications.

According to another aspect of the invention there is provided the use of an aqueous, mixed oxidant, predominantly anion-containing solution in the treatment of acute and chronic infectious cystitis, wherein the aqueous, mixed oxidant, predominantly anion- containing solution is infused or instiled into the lumen of a urinary bladder; and wherein maximal contact between infectious microbial agents and the solution is achieved through a process of hydrodistention.

According to another aspect of the invention there is provided the use of an aqueous, mixed oxidant, predominantly anion-containing solution in the preparation of a medicament for use in the treatment of acute and chronic infectious cystitis.

According to a further aspect of the invention there is provided the use of an aqueous, mixed oxidant, predominantly anion-containing solution in the treatment of acute and/or chronic, superficial and/or interstitial, infectious and/or inflammatory conditions of the urinary bladder and its associated anatomical architecture.

According to another aspect of the invention there is provided the use of an aqueous, mixed oxidant, predominantly anion-containing solution in the preparation of a medicament for use in the treatment of acute and/or chronic, superficial and/or

interstitial, infectious and/or inflammatory conditions of the urinary bladder and the associated anatomical architecture.

According to yet a further aspect of the invention there is provided an aqueous, mixed oxidant, predominantly anion-containing solution characterised therein that it possesses distinctive anti-inflammatory properties and is suitable for use either as an instillation or as an infusate for controlling or resolving inflammatory and hyperaesthetic urine voiding symptoms and for reducing or resolving clinical haemorrhagic and histopathologic symptoms associated with repeated radiation therapies.

According to yet a further aspect of the invention there is provided the use of an aqueous, mixed oxidant, predominantly anion-containing solution in controlling or resolving inflammatory and hyperaesthetic urine voiding symptoms and for reducing or resolving clinical haemorrhagic and histopathologic symptoms associated with repeated radiation therapies.

According to yet a further aspect of the invention there is provided a method of treatment of a human or animal body suffering from acute and/or chronic microbially induced cystitis, the method including the steps of electrochemically activating a dilute aqueous solution such that the electrochemically activated, aqueous solution includes separable and both of an aqueous, mixed oxidant, predominantly anion-containing solution and an aqueous, mixed reductant, predominantly cation-containing solution; separating the aqueous, mixed oxidant, predominantly anion-containing. solution from the aqueous, mixed reductant, predominantly cation-containing solution; infusing or instiling the aqueous, mixed oxidant, predominantly anion-containing solution into lumen of a urinary bladder of the human or animal body; and through a process of

hydrodistention optimising contact between the infused or instiled aqueous, mixed oxidant, predominantly anion-containing solution and the entire bladder mucosal surface so as to ensure maximal contact between infectious microbial agents and the solution.

The method may include the additional step of infusing or instiling the aqueous, mixed reductant, predominantly cation-containing solution into lumen of the urinary bladder of the human or animal body after treatment of the same with the aqueous, mixed oxidant, predominantly anion-containing solution.

According to yet a further aspect of the invention there is provided a method of treatment of a human or animal body suffering from acute and/or chronic immunogenic and radiation induced cystitis, the method including the steps of electrochemically activating a dilute aqueous solution such that the electrochemically activated, aqueous solution includes separable and both of an aqueous, mixed oxidant, predominantly anion-containing solution and an aqueous, mixed reductant, predominantly cation- containing solution; separating the aqueous, mixed oxidant, predominantly anion- containing solution from the aqueous, mixed reductant, predominantly cation-containing solution; infusing or instiling the aqueous, mixed reductant, predominantly cation- containing solution into lumen of a urinary bladder of the human or animal body; and through a process of hydrodistention optimising contact between the infused or instiled aqueous, mixed reductant, predominantly cation-containing solution and the entire bladder mucosal surface so as to ensure maximal contact between the bladder wall and the solution.

The method may include the additional step of infusing or instiling the aqueous, mixed oxidant, predominantly anion-containing solution into lumen of the urinary bladder of the

human or animal body after treatment of the same with the aqueous, mixed reductant, predominantly cation-containing solution.

According to yet a further aspect of the invention there is provided a method of treatment of a human or animal body suffering from acute and/or chronic cystitis, the method including the steps of electrochemically activating a dilute aqueous solution such that the electrochemically activated, aqueous solution includes separable and both of an aqueous, mixed oxidant, predominantly anion-containing solution and an aqueous, mixed reductant, predominantly cation-containing solution; separating the aqueous, mixed oxidant, predominantly anion-containing solution from the aqueous, mixed reductant, predominantly cation-containing solution; infusing or instilling, at a rate of approximately 150m !/hour, 2 litres of a solution comprising substantially equal parts by volume of the aqueous, mixed reductant, predominantly cation-containing solution and the aqueous, mixed oxidant, predominantly anion-containing solution and diluted to 50% strength with normal saline, into lumen of a urinary bladder of the human or animal body; and through a process of hydrodistention optimising contact between the infused or instiled aqueous, mixed solution and the entire bladder mucosal surface so as to ensure maximal contact between the bladder wall and any associated infectious microbial agents, and the solution.

According to yet a further aspect of the invention there is provided a method of treatment of a human or animal body suffering from acute and/or chronic, superficial and/or interstitial, infectious and/or inflammatory conditions of the urinary bladder and its associated anatomical architecture, the method including the steps of electrochemically activating a dilute aqueous solution such that the electrochemically activated, aqueous solution includes separable and both of an aqueous, mixed oxidant, predominantly

anion-containing solution and an aqueous, mixed reductant, predominantly cation- containing solution; separating the aqueous, mixed oxidant, predominantly anion- containing solution from the aqueous, mixed reductant, predominantly cation-containing solution ; infusing or instiling the aqueous, mixed oxidant, predominantly anion- containing solution into lumen of a urinary bladder of the human or animal body; and through a process of hydrodistention optimising contact between the infused or instiled aqueous, mixed oxidant, predominantly anion-containing solution and the entire bladder mucosal surface so as to ensure maximal contact between infectious microbial agents and the solution.

The method may include the additional step of infusing or instiling the aqueous, mixed reductant, predominantly cation-containing solution into lumen of the urinary bladder of the human or animal body after treatment of the same with the aqueous, mixed oxidant, predominantly anion-containing solution.

Specific embodiment of the invention Experiments were conducted on patients with intractable and recurrent interstitial cystitis that had proven to be refractory to all current and traditional means of therapeutic intervention.

Inflammation of the bladder wall present in patients suffering from cystitis can result from one or more of three main causes, namely due to microbial infections, immunogenic causes or due to external radiation, for example during cancer treatment.

Each of these causes of cystitis is characterised therein that is responds to specific optimal treatment methods. Microbially induced cystitis responds best to treatment by anolyte which comprises anti-microbial properties, whereas the immunogenic and

radiation induced cystitis would respond better to treatment by catholyte, which has anti- oxidant properties and promotes healing.

However, the applicant has found that although anolyte treatment is sufficient in microbially induced cystitis, and catholyte in immunogenic and radiation induced cystitis, treatment of patients with the other one of the two solutions (catholyte or anolyte, as the case may be) in both cases have increased recovery. It is believed that this is so because of the following reasons. After the causative microbes have been eradicated by treatment with the anolyte in the case of microbially induced cystitis, follow-up treatment with catholyte promotes quicker and more complete healing. Similarly, in the case of immunogenic and radiation induced cystitis, treatment with anolyte, in conjunction with treatment with catholyte, will ensure eradication of any opportunistic infectious agents.

Example : Fifteen patients with chronic progressive Interstitial Cystitis (IC) were treated according to the following protocol.

All patients were admitted for overnight evaluation and an indwelling catheter was inserted into the bladder. The following morning, the freshly generated, mixed oxidant anolyte solution (pH=7, ORP=+750mV) was diluted to a 50% strength with normal saline (0,9% m/v) and 1000ml of the 50% strength solution was infused into the bladder lumen for 6 hours. In patients where the chronic nature of the condition had reduced bladder capacity to less than 1000ml, the maximum volume to accommodate the reduced bladder capacity was administered as an instillation. The mixed oxidant perfusate was subsequently drained from the bladder and flushed with 100mi of sterile

saline (0,9% m/v).

Thereafter 1000ml of the mixed predominantly anti-oxidant radical catholyte solution (pH=11, ORP=-850mV) was infused into the bladder by way of the indwelling catheter for a further six-hour period.

Following drainage of the anti-oxidant solution, and removal of the indwelling catheter, the patients were discharged from the medical facility.

Of the fifteen patients treated to date, no relapse of symptoms of the original condition have occurred and all patients have reported a significant improvement in urine retention capacity, reduced frequency of voluntary bladder emptying, and an extended duration of inter-voiding interval. These significant improvements were achieved without perpetuation of the adjunct antimicrobial and analgesic therapy prescribed for the original condition.

The use of electrochemically activated aqueous solutions as direct infusions or instillations has been shown to offer significant relief or resolution of clinical disease of the urinary bladder and associated anatomical architecture as may be associated with chronic inflammation arising from neurogenic voiding dysfunction, intractable haemorrhagic cystitis secondary to pelvic radiation therapy, and chronic recurrent cystitis of various non-specific microbial and/or inflammatory aetiologies It will be appreciated that many variations in detail are possible without departing from the scope or spirit of the invention as defined in the claims.