Interstitial Cystitis / Bladder Pain Syndrome
Interstitial Cystitis/Bladder Pain Syndrome
OTRIMED IS OFFERING A NEW PAIN TREATMENT OPTION FOR PATIENTS SUFFERING FROM INTRACTABLE INTERSTITIAL CYSTITIS/ BLADDER PAIN SYNDROME.
Otrimed Research Center is currently RECRUITING patients for a multicenter, randomized, double-blind, placebo-controlled, crossover study to investigate the effect of oral administration of 1 mg/day of an investigational product in female subjects with a diagnosis of interstitial cystitis/bladder pain syndrome as compared to placebo.
TARGET PATIENTSPatients with symptoms of bladder pain greater than 4 but less than 9
STAGE OF THE STUDYPhase 1B
About The Study
INTERSTITIAL CYSTITIS is characterized by pain or discomfort related to the bladder with accompanying lower urinary tract symptoms such as frequency, urgency, and nocturia, in the absence of malignancy, endometriosis, chronic prostatitis, and bladder outlet obstruction.
Patients diagnosed with Interstitial Cystitis should contact Otrimed (www.otrimedresearchcenter.com) for a free evaluation. An Urologist must make the diagnosis of IC/BPS by Cystoscopy. ● The patient should have symptoms of bladder pain greater than 4 but less than 9 on a 0 – 10 pain intensity scale where 0 is no pain and 10 is the worst imaginable pain. ● The patient should have a history of voiding at least more than ten times and less than 30 times per day
Protocol
Multicenter, Randomized, Double-Blind placebo-controlled, crossover study to investigate effects of V117957 in female subjects with interstitial cystitis: Bladder pain syndrome. Phase 1B study.
The study's primary objective is to determine the efficacy of the investigational product in controlling pain. The product does not cure the disease per se.
INCLUSION AND EXCLUSION CRITERIA FOR THE STUDY PARTICIPATION: To participate in the trial following inclusion criteria need to be satisfied: ● Be female, nonpregnant, 18 – 64 yrs. Age, capable of voiding independently. Able to comply with acceptable methods of contraception. ● Have a diagnosis of IC/BPS per American Urology Association Guidelines that was documented in the subject's medical records at least six months before screening. ● Have bladder pain/discomfort with accompanying lower urinary tract symptoms that meet the following criteria at screening: - The subject has a complaint of bladder pain/pressure/discomfort for greater than 6 months accompanied by other lower urinary tract symptoms for more than 6 months and - The subject has a bladder pain/interstitial cystitis symptoms scale total score of more than 19 and - The subject's daily average bladder pain/discomfort score during the past week is greater than 4 and less than 9 as rated by the subject using an 11-point NRS that ranges from 0 = no bladder pain/discomfort to 10 = as bad as you can imagine bladder pain/discomfort and, - Subject micturition frequency is estimated to be greater than 11 and less than 30 voids per 24 hours in the last week. ● Has cystoscopy findings been obtained within 9 months of screening, that exclude other conditions that cause bladder pain discomfort (e.g., transitional cell carcinoma of the bladder, endometriosis of the bladder). Note: a subject is not required to have Hunner's lesion on bladder cystoscopy for inclusion into the study. ● The subject should: - Not have received pharmacologic Treatment for IC/BPS in past 30 days: or, - Maybe on oral pharmacologic Treatment for IC/BPS at a stable dose /regimen for the past 30 days and in the judgment of P.I., is expected to remain on the same stable dose/ regimen throughout the study. ● Meet study inclusion criteria despite a history of previous or continuing treatments including conservative Treatment, which may include one or more of the following: - Timed voiding and behavioral modification therapy, - Dietary restrictions - Stress reduction - Despite oral therapy with any of the following: antidepressants, antihistamines, antimuscarinic and anticholinergic agents, alpha-adrenergic blockers, analgesics, and pentosan polysulfate.● Should be otherwise healthy.
Overview of Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS)
It is a chronic bladder condition comprising of recurring discomfort or pain in the Urinary bladder or in the pelvis. It is commonly characterized by persistent pelvic pain and lower urinary tract symptoms such as urinary frequency and urgency. The urinary bladder wall gets inflamed; in extreme cases, inflammation of the wall may result in scarring and stiffening of the urinary bladder needing extensive surgery.
Epidemiology: Since the exact cause is still unknown and lacks definitive biomarkers, it is hard to determine the incidence of the disease. However, according to the CDC website, updated epidemiologic research conducted in 2006 suggests that up to 12% of women may have early symptoms of I.C.
The Investigative Product VII7957 is a selective partial agonist of the Nociceptin /orphanin -F.Q. peptide receptor. It inhibits bladder afferents following systemic administration in rats leading to a reduction in the frequency of rhythmic bladder contractions without affecting the magnitude of contraction. It has demonstrated an antinociceptive effect in animal models of interstitial cystitis.
Mechanism of Action of the Investigational product
The Investigational product is an agonist of the Nociceptin/orphanin -F.Q. Peptide receptor (N/OFQ peptide – or NOP receptor).
This receptor is widely distributed in the peripheral and central nervous system (Central N/OFQ-NOP Receptor System in Pain Modulation - Kiguchi et al, page 219), it is also expressed in the ventral and dorsal horn of the spinal cord, which integrates sensory processing (Neal et al 1999b).
Unlike classic opioid receptors such as MOR (Mu opioid receptors), KOR (Kapa Opioid Receptor), and DOR (delta Opioid receptor), the NOP receptor does not display opioid pharmacology. The binding pocket of NOP differs from those of MOR, KOR, and DOR (Grainer et al 2012). The hydrophobic and hydrophilic parts of the binding pockets of the NOP receptor and other Opioid receptors are distinctly different. Therefore, the binding selectivity of ligand to the NOP receptor is distinctly different than the classic MOR, KOR, and DOR even though the structural homology between NOP receptor and the classic opioid receptors (Calo & Guerrrini 2013).
This product lacks major side effects that are commonly seen associated with MOP receptor agonists. Selective NOP receptor agonists display a much wider therapeutic window than MOP receptor agonists in primates (Lin & Ko, 2013).
The cellular mechanism of action is the same as that of the classic opioid receptors. NOP receptor coupled to pertussis toxin-sensitive Gi/o proteins inhibits adenylate cyclase and voltage-gated calcium channels and activates inward potassium channels. (Hawes, Graziano, & Lambert, 2000; Ma et al., 1997; Margas, Sedeek, & Ruiz-Velasco, 2008).
These cellular events following NOP receptor activation reduce synaptic transmission, by either reducing neurotransmitter release via presynaptically located NOP receptors or inhibiting neuronal excitability via postsynaptically located NOP rectors (Connor, Vaughan, Cheng, & Christie, 1996).
Bibliography
● Grainer. S, Manglik, A., Kruse, A.C., Kbilka, T.S et al. Structure of the delta-opioid receptor bound to naltrindole. Nature, 485(7398), 400-404).
● Kiguchi et al, Central N/OFQ-NOP Receptor System in Pain Modulation, Advances in Pharmacology Volume 75 Page 217- 243.
● Calo, G., Guerrini, R., et al, 2013. Medicinal chemistry, pharmacology, a biological action of peptide ligands selective for Nociceptin/orphanin FQ receptor. In M.C. Ko & S.M. Husbands (Eds.), ACS symposium series: Vol 1131. Research and development of opioid-related ligands (pp.275-325). Washington, DC: American Chemical Society.
● Lin, A.P., Ko, M.C. (2013). The therapeutic potential of Nociceptin/orphanin FQ receptor agonists as analgesics without abuse liability. ACS Chemical Neuroscience 4(2), 214-224.
● Hawes, B.E., Graziano, M.P., & Lambert. D.G. (2000). Cellular action of Nociceptin: Transduction mechanism. Peptides, 21(7), 961-967.
● Margas, W, Sadeek, K. et al (2008). Coupling specificity of NOP opioid receptors to pertussis-toxin-sensitive G alpha proteins in adult rat stellate ganglion neurons using small interference RNA. Journal of Neurophysiology, 100(3), 1420-1432.
● Schrӧder, W., Lambert, D.G., et al (2014). Functional plasticity of the N/OFQ-NOP receptor system determines the analgesic properties of the NOP receptor agonist. British Journal of Pharmacology, 171(16), 3777-3800.
Read More
The American Urological Association (AUA) defines IC/BPS as an unpleasant sensation (pain, pressure, or discomfort) perceived to be related to the urinary bladder and associated with lower urinary tract symptoms lasting > 6 weeks in the absence of infection or other identifiable cause. IC/BPS is classified based on the cystoscopy/ histological findings based on bladder biopsy associated with the Hunner lesions ('classic' or ulcerative I.C., without Hunner lesions but with glomerulations, and with neither Hunner lesions nor glomerulations.
IC/BPS with Hunner lesions is characterized by pan cystitis with epithelial denudation, whereas IC/BPS without Hunner lesions exhibits minimal inflammatory changes and has preserved Urothelial cells.
IC/BPS with Hunner lesions is a distinct inflammatory disorder characterized by pan cystitis with frequent clonal expansion of infiltrating B cells and epithelial denudation. IC/BPS without Hunner lesions is a noninflammatory disorder with a disorder of lamina propria (fibrosis). ● Akiyama et al. Pathology and terminology of interstitial cystitis/bladder pain syndrome: A review. Histol Histopathol (2019) 34: 25 – 32.
The exact etiology or cause of the disease is not known. Treatment Guidelines per American Urological Association (revised in 2014):
The first line of Treatment: ● According to the American Urological Association, no single treatment has been found to be effective.● Conservative Treatment is the mainstay of the Treatment. ● The patient should be educated about bladder function. ● Self-care practices and behavioral modifications that can improve symptoms should be discussed and implemented as feasible. ● Stress management, improve coping techniques and manage symptoms-induced stress management.
The Second Line of Treatment: ● Appropriate manual physical therapy techniques. Pelvic floor strengthening exercises (e.g., pharmacological, stress management, manual therapy if available) should be initiated. ● Amitriptyline, cimetidine, hydroxyzine, or pentosan polysulfate may be administered as a second line of Treatment. ● Intravesical DMSO, Heparin, or lidocaine may be administered.
The Third line of Treatment: ● Cystoscopy under anesthesia, low-pressure hydrodistension once the above options have failed. ● If Hunner's lesions are present, then fulguration with laser or electrocautery and or injection of triamcinolone.
The Fourth line of Treatment: ● Intra-detrusor botulinum toxin-A if the above options have failed. The patient should be prepared to self-catheterize if necessary (evidence strength C).● Trial of Neurostimulation if all the above options failed. If the trial is successful, then implantation of permanent NEUROSTIMULATION (evidence strength C)
The Fifth line of Treatment: ● Cyclosporine A may be administered as oral medication (evidence strength C).
The Sixth line of Treatment: ● Major surgery such as Substitution cystoplasty, and urinary diversion with or without cystectomy in carefully selected patients (evidence strength C).
Treatment that Should Not be Offered: ● Long-term oral antibiotic● Intravesical instillation of BCG. ● High-pressure long, duration hydrodistension ● Systemic oral long-term glucocorticoid administration.
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