As mentioned, chemical injury of the normal bladder surface mucus will cause an injury to the barrier effect of the epithelium [2–5, 7–10]. It was also discovered that this injury in both rodents and humans can be reversed with an intravesical treatment of the bladder surface with either heparin of pentosanpolysulfate (PPS) [2, 4, 5, 7–10, 26]. As a direct result of these observations it was hypothesized that heparinoids might beneficially impact on diseases where the mucosa was dysfunctional such as interstitial cystitis. PPS has an oral form that is about 2.5% bio-available. It was then tried in several opened labeled and a double blind study [13] to determine if it had efficacy in IC and the drug was successful at relieving symptoms after several months of therapy [27, 28]. Bear in mind that in the early 1980s when these initial studies were done IC for the most part was only recognized in its severe form where symptoms were chronic and unrelenting. It was 20 plus years later that IC was indeed discovered to have a beginning where symptoms are mild and intermittent [29]. And In this early phase is far more common than the rare severe but classical form of IC. So the initial experience with IC was on the severe patients and the positive results that were obtained were quite promising. These studies led to key pivotal clinical trials. The company conducting the trials met with the United States Food and Drug Administration (FDA) and developed a protocol that was acceptable to the FDA. Basically the two trials were randomized, prospective, multi-centered placebo controlled trials. The entry criteria were strictly defined and utilized the NIDDK criteria which were developed shortly before these clinical trials began. These two studies used the the Global Assessment Response of symptoms (known as the GAR) as the primary outcome measure which was first reported by Parsons [13]. The GAR was statistically validated as an outcome measure for IC clinical trials in the larger of these two studies [12] and is now widely used for this purpose. Patients entered were defined as having severe disease for at least 1 year with moderate or worse symptoms of pain and urgency, had a cystoscopy under anesthesia, completed a 3 day voided log (at the beginning and end of the trial) and were begun on PPS 100 mg TID for 3 months. At the end of the study the global assessment of symptoms questionnaire was filled out by each patient. It is a six point scale with patients reporting (1) worse (2) 0% improved (3) 25% improved (4) 50% improved (5) 75% improved (6) 100% improved. Better was predefined in the protocols as 50% or greater improvement and those not reaching this level were deemed no better. The percent of patients reporting better is summarized in Table 26.2 for each study. These studies were the basis for approval of PPS to treat IC by the Food and Drug Administration in the United States in 1996.

PPS should be the basis for any single or multimodal therapy for IC since it treats the root cause of IC the epithelial dysfunction [30]. Severe patients usually require the multiple therapy approach to address both the epithelial problem and their symptoms. The approved dosage of PPS is 300 mg per day. A subsequent study showed that longer durations of therapy up to 8 months resulted in a higher success rate of improvements in patients up to 70% [31]. Currently, I routinely start female patients on 200 mg of PPS BID and if not better in 4 months increase the dose to 300 mg BID. For severe patients if not better at 6–8 months I will increase it to 300 mg TID. Males I routinely start on 300 mg BID. I never stop the PPS until the patients lose all or most of the symptoms but frequently add other therapies to control their symptoms. In general PPS (or other heparinoids) are the only drugs the reverse the course of the disease and reduce the epithelial leak of potassium allowing the bladder to heal [30]. It should always be the primary foundation of therapy. It is important to have patience and continue therapy and encourage people (especially patients with many years of severe symptoms) to stay on treatment indefinitely even years before success may be obtained. Explaining to the patient that PPS can reverse the course of the disease is helpful so that they realize that staying on the medication is critical along with other treatment modalities that may be added to their therapeutic regimen. PPS has been on the Unites States market for over 20 years. This long experience with the drug has shown that it is very benign and well tolerated and has been used in well over 100,000 people with an excellent safety profile in both the low and high doses of medication reported herein.

I have reported successful use of PPS in 42 children and the dose by weight that I have employed is presented in Table 26.3 [32]. In General children responded quicker and better to therapy which is probably not surprising since they have had disease for a shorter time and tend to heal faster than do adults.