Evaluation of Response to Use of Intravesical Ozone Gas in Interstitial Cystitis /Bladder Pain Syndrome
Evaluation of Response to Use of Intravesical Ozone Gas in Interstitial Cystitis /Bladder Pain Syndrome
Interstitial Cystitis / bladder pain syndrome (CI / BPS) is a debilitating pathology with a
 negative impact on the quality of life of affected individuals. It is characterized as the
 sensation of pain or discomfort related to the urinary bladder, accompanied by symptoms of
 the lower urinary tract, in the absence of infection. Among the phenotypes are Cystitis with
 Hunner's ulcer, essentially inflammatory pathology and without Hunner's lesion,
 non-inflammatory frequently associated with somatoform systemic changes. Functional changes
 in urothelium and epithelial barrier, neurogenic inflammation and autoimmune mechanisms are
 involved in the development of the disease.

 Medical ozone has anti-inflammatory, antioxidant, cytoprotective, antimicrobial and
 immunomodulatory properties. When administered, it is dissolved in biological fluids,
 immediately reacting with glycoproteins composed of carbohydrates and polypeptide chains.
 This reaction results in the formation of hydrogen peroxide (H2O2), lipid oxidation products
 (LOS), increased activation of erythroid-related nuclear transcription factors (Nrf2)
 activation of antioxidant response transcription elements (ARE) and increased variety of
 antioxidant enzymes that act as free radical scavengers. Benefits of O3 have been
 demonstrated in the treatment of neuropathic pain and hyperalgesia associated with the
 analgesic and anti-inflammatory effect.

 The objective of this work is to evaluate the effect of intravesical ozone gas administration
 in patients with Interstitial Cystitis / Painful Bladder Syndrome with low response to
 conventional therapy.
Interstitial Cystitis / bladder pain syndrome (IC / BPS) is a debilitating pathology with a
 negative impact on the quality of life of patients. According to the European Society for the
 Study of IC / BPS (ESSIC) it is expressed as a sensation of pain, pressure or discomfort
 related to the urinary bladder accompanied by symptoms of the lower urinary tract. Symptoms
 occur in the absence of infection and obvious pelvic pathologies lasting more than six weeks.

 The CI / BPS has a variety of clinical phenotypes and potential etiologies. Among the
 phenotypes are included cystitis (IC) associated with Hunner's ulcers, known as ESSIC BPS
 type 3 and without Hunner's lesion, ESSIC type 1,2. Differentiation between the sub-types is
 performed through cystoscopy by the presence or absence of Hunner's lesions.

 The dysfunctions resulting from IC / BPS originate around the bladder, adjacent pelvic organs
 and part of the neural tissue that controls bladder function. Functional changes in
 urothelium and epithelial barrier, neurogenic inflammation and autoimmune mechanisms are
 involved in the development of the disease.

 The urothelium is covered by a layer of glycosaminoglycans (GACs) forming a protective
 barrier to the underlying tissues against urinary constituents and promoting selective
 control of molecules towards the bladder wall.

 Molecular and structural changes in the GACs layer associated with the inflammatory process
 cause changes in urothelial permeability allowing toxic substances and urinary cations to
 reach the muscle and neural layer. The loss of the urothelial barrier allows chemical,
 cytotoxic stimuli to come into direct contact with peripheral bladder afferent neurons with
 persistent sensitization, central nervous amplification and local inflammatory reaction.

 Neurotransmitters released by peripheral neurons, including vasoactive peptides, calcitonin
 and tachykinins induce mast cell degranulation and release of pro - inflammatory mediators
 such as histamine, serotonin, tryptase, TNF-α and NGF, IL6 resulting in local inflammation.
 These inflammatory mediators act on afferent neurons in a positive feedback loop resulting in
 the release of neurotransmitters that exacerbate mast cell degranulation and local
 inflammatory response, with functional destruction of bladder tissue, fibrosis, low Detrusor
 compliance and hyperactivity.

 Alterations in the Autonomic Nervous System with sympathetic hyperactivity and exacerbation
 of the sensation of pain induces a condition of hyperalgesia associated with stress, in
 addition to contributing to the maintenance and worsening of the functional changes of the
 bladder. Persistent spinal cord activation can mediate pain after resolution of the
 inflammatory process.

 The bladder pain syndrome is a common cause of chronic pelvic pain. It presents low long-term
 therapeutic response, innovative therapeutic modalities in the field of current studies.

 Ozone gas (O3) is a molecule made up of three oxygen atoms with an unstable structure given a
 mesomeric effect. It has an average life of 40min at 20º C.

 The interest in the therapeutic use of O3 in several diseases is growing. This interest is
 associated with anti-inflammatory, cytoprotective, antioxidant, antimicrobial and
 immunomodulatory properties. Animal models suggest beneficial and prophylactic effects of O3
 therapy on age-related oxidative stress.

 When administered, O3 is dissolved in biological fluids, reacting immediately with
 glycoproteins composed of carbohydrates and polypeptide chains (proteoglycans, collagen types
 II and IV). This reaction results in the formation of hydrogen peroxide (H2O2), lipid
 oxidation products (LOS), increased activation of erythroid-related nuclear transcription
 factors (Nrf2) activation of antioxidant response transcription elements (ARE) and increased
 variety of antioxidant enzymes that act as free radical scavengers.

 Benefits of O3 have been demonstrated in the treatment of neuropathic pain and hyperalgesia
 associated with the analgesic and anti-inflammatory effect. Animal models demonstrate
 decreased and normalized expression of caspases and IL -1β, TNF. At low doses, O3 reduces the
 synthesis of prostaglandins (PGS) by inhibiting prostaglandin endoperoxide synthase (PGHS2)
 and cyclooxygenase (COXs). This fact is critical in preventing neural sensitization following
 persistent stimulation of intracellular pathways responsible for the excessive release of
 cytokines, PGs, or glutamate.

 ETHICAL CRITERIA. All patients must undergo the signature of the Informed Consent Form for
 Medical Treatment with Medicinal Ozone METHODOLOGY This is an interventional, controlled
 study that provides for the application of intravesical ozone gas as an alternative treatment
 for patients with interstitial cystitis/bladder pain syndrome The study foresees the
 participation of 50 patients with interstitial cystitis /bladder pain syndrome and will be
 developed in the Hospital Unit of Nephrology and Urology Distal, located in the city of
 Jacareí, São Paulo, Brazil.

 DIAGNOSTIC CRITERIA 1.1 History A thorough general medical history to identify typical
 diagnostic symptoms of Interstitial cystitis and bladder pain syndrome and other potential
 mimicking causative conditions. Figure 1 shows a flowchart of clinical approach.

 1.2 Physical examination The physical exam include an abdominal and pelvic exam, with
 particular focus for masses, bladder distension and suprapubic tenderness. In men,
 sensitivity will be analyzed through palpation of the perineal area between the scrotum and
 anus. In women sensitivity will be analyzed through palpation of the anterior vaginal wall
 along the course of the urethra up to the bladder neck.

 1.3 DIAGNOSTIC METHODS A. Urinalysis and Culture A urine dipstick will be performed on all
 patients The laboratory method of qualitative and quantitative determination of pathogenic
 microorganisms in the urinary tract will be performed. Urinary tract infection will be
 characterized by the bacterial growth of at least 105 Colony Forming Units per ml of urine
 (100.000 CFU / mL). The collection of urinary sample will be performed with aseptic technique
 avoiding contamination with the microbiota of the perineum, prostate, urethra and vagina.

 B. Ultrasound Urinary Tract Abdominal and pelvic ultrasonography will be performed on all
 patients. C. Urodynamic Assessment Study carried out with the purpose of obtaining functional
 information on vesical storage and emptying.

 D Symptom scores Symptom score IC / BPS will be used to establish a baseline of symptom
 severity at admission and subsequently, track response to treatment and disease relapse. It
 Will be used in the O'Leary-Sant Symptom and Problem Index, that is validated and widely used
 as a self-report measure of urinary and pain symptoms and how problematic these symptoms are
 for individuals. The measure assesses both symptoms and problems of IC/BPS each with four
 questions, yielding a symptom score (ICSI), problem score (ICPI), and total severity score.
 Symptom scores (ICSI) range from 0 to 21 and problem scores (ICPI) range from 0 to 16, with a
 total ICSI/ICPI combined score ranging from 0 to 37[21].

 TREATMENT PROTOCOL Patients who meet inclusion criteria will be subjected to conventional
 treatment of the diagnoses made and submitted to the application of intravesical medicinal
 ozone gas.

 Therapeutic Scheme

 1° Bladder wash with 0.9% Saline - 500 ml performed through urethral tube n° 10; 2° Bladder
 emptying ; 3° Medical Ozone gas infusion 20 µg / ml - 60ml, intravesical forecast of two
 weekly sessions, with a total of six applications.

 Clinical Follow-up Patients will be evaluated at each session using the score IC/BPS and
 possible side effects. At the end of the sixth session, Uroculture and Urofluxometry will be
 scheduled.

 Monthly assessments will be scheduled for up to six months from the end of treatment to
 verify the maintenance of therapeutic response over time DATA ANALYSIS Qualitative data will
 be grouped into categories followed by the corresponding percentage. The analysis will be
 performed using SPSS software and Microsoft Excel.

 Quantitative data will be presented in frequency distribution tables with mean, median and
 descriptive statistics. Statistical analysis performed using Student's t-test with
 significance values p> 0.05.

 CLINICAL RISK It is a risk procedure estimated as small since the administration of Ozone
 with controlled doses is safe and determinant of small side effects. The discomfort caused by
 the use of the urethral tube is small and performed safely.

 The specialized professionals who will conduct the experiments will be available and able to
 offer any necessary attention BENEFIT Patients who will be included in the present study have
 chronic pathology with impaired quality of life and inadequate response to conventional
 therapy. Based on scientific evidence, Ozone Therapy is expected to be a treatment
 alternative.
Inclusion Criteria:

 -  Interstitial Cystitis

 -  Bladder pain Syndrome

 Exclusion Criteria:

 -  Malignant Neoplasm

 -  Bladder Lithiasis.

 -  Lower Tract Infections