Biomedical subjects
Publications and source records attributed to C Lowell Parsons.
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AIM: Loss of the lower urinary permeability barrier and passive potassium cycling into tissue are an initiating event in interstitial cystitis. We tested whether a low molecular weight cytotoxic fraction from normal urine causes sensitivity to intravesical potassium in rats and whether the sulfated anionic polysaccharide pentosan polysulfate can neutralize this fraction's cytotoxic activity. METHODS: A low molecular weight (> 100 < 3500) toxic urinary fraction was prepared from normal human urine by dialysis and the lyophilized, salt free product (toxic factor) further investigated. Anaesthetized adult male Sprague-Dawley rats received intravesical sodium or potassium, and urodynamic parameters, including number of voids and non-voiding contractions, were recorded. Then protamine sulfate, rehydrated toxic factor, or toxic factor plus pentosan polysulfate was infused, followed by potassium, and urodynamic measurements repeated. The toxic factor was evaluated in a commercial cytotoxicity protocol using cultured rat urothelial cells. RESULTS: Rat bladder non-voiding contractions increased markedly over baseline when potassium was infused after toxic factor (1.681 +/- 0.1131 non-voiding contractions/min; P = 0.0004) but not after toxic factor premixed with pentosan polysulfate. Toxic factor had a significant (P < 0.001) cytotoxic effect in cultured rat bladder epithelial cells; toxic factor plus pentosan polysulfate was significantly less cytotoxic than toxic factor alone (P < 0.007). CONCLUSIONS: Normal urine contains a cationic cytotoxic factor that increases urothelial permeability by injuring the mucosa, allowing potassium to penetrate the urothelium and depolarize the underlying nerves and muscles. Pentosan polysulfate neutralizes the toxic factor, attenuates urothelial damage, and suppresses potassium-mediated bladder hyperactivity.
OBJECTIVE: To evaluate the effects of MN-001, a novel orally active anti-inflammatory agent, in suppressing the bladder hyperactivity resulting from ovalbumin (OA)-induced mast-cell stimulation in a rat model. MATERIALS AND METHODS: Sprague-Dawley rats of both sexes were divided into five groups of 10 each, with group 1 as the control and groups 2-5 undergoing OA sensitization to produce mast-cell degranulation using an established method. At 14 days after sensitization, rats were given an acute intravesical challenge: in group 1, by saline (control), and in groups 2-5, with approximately 2 mL of OA (10 mg/mL in sterile saline). Groups 3-5 received the investigational agent MN-001 orally at 10, 30 or 50 mg/kg, respectively, 1 h before intravesical OA challenge. Urodynamics were then evaluated to quantify the frequency of contractions (voids), intercontractile interval (ICI) and non-voiding contractions (NVCs). RESULTS: Acute intravesical OA challenge in rats in group 2 caused contractions of bladder smooth muscle, leading to a significant (P < 0.05) dose-dependent increase in NVCs and a decrease in ICI. Rats pre-treated with MN-001 at 30 and 50 mg/kg (groups 4 and 5) had significantly fewer NVCs and a greater ICI than rats in group 2 (P < 0.05). CONCLUSION: OA challenge in OA-sensitized rats produces bladder hyperactivity, as reflected in significantly more NVCs and a lower ICI. At doses of 30 and 50 mg/kg orally, MN-001 produces significant protection against the OA-induced bladder hyperactivity. MN-001 might have a role in managing mast cell activity and the associated bladder symptoms in patients with interstitial cystitis.
Recent years have brought dramatic advances in the clinician's ability to offer effective pharmacotherapy to patients who have interstitial cystitis. Medical treatments have been developed and applied to reduce the interstitial cystitis symptoms of pelvic pain and urinary urgency/frequency, and to address underlying causes of the disorder. In addition, advances in the understanding of the natural history of interstitial cystitis have revealed that it is insidiously progressive and the classical definition--rare, severe and difficult to treat--is in fact the relatively uncommon, advanced stage of a disorder that affects most individuals in a mild-to-moderate and readily treatable form. This recognition has led to the identification of large numbers of previously unsuspected cases of interstitial cystitis, and the successful treatment of many individuals in the early stages of interstitial cystitis when it is far more responsive to therapy. A heparinoid-based multimodal medical regimen can effectively control symptoms and address disease pathophysiology in the majority of cases. Intravesical therapeutic solutions are new and promising adjunctive therapies that can offer immediate symptom relief during symptom flares, and for patients who are just beginning medical therapy.
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OBJECTIVES: To test the efficacy of a new intravesical therapeutic solution in relieving urgency/frequency and pain in interstitial cystitis (IC). METHODS: A solution of 40,000 U heparin, 8 mL 1% lidocaine (80 mg; group 1) or 2% lidocaine (160 mg; group 2), and 3 mL 8.4% sodium bicarbonate was administered intravesically in patients with newly diagnosed IC with significant frequency, urgency, and pain. Using the Patient Overall Rating of Improvement of Symptoms, the response to treatment was evaluated within 20 minutes of instillation in all patients, after 24 to 48 hours in group 2, and after three treatments per week for 2 weeks in group 2 patients who elected to receive additional instillations. Significant symptom relief was defined as 50% or greater symptom improvement. RESULTS: After one instillation, 35 (75%) of 47 patients in group 1 (1% lidocaine) and 33 (94%) of 35 in group 2 (2% lidocaine) reported significant immediate symptom relief. The difference in the response rates was statistically significant (P <0.01). In group 2, 50% of the subjects experienced at least 4 hours of symptom relief from the single instillation, and 16 (80%) of 20 reported significant sustained symptom relief after 2 weeks of treatment. CONCLUSIONS: Intravesical treatment with combined heparin and alkalinized lidocaine immediately reduced the pain and urgency of IC in most patients treated for newly diagnosed IC. Symptom relief lasted beyond the duration of the local anesthetic activity of lidocaine, suggesting the solution suppresses neurologic upregulation. In IC treatment, this new intravesical solution may be helpful in the interval before heparinoid therapy reaches its full effect.
OBJECTIVES: To compare the current recommended dose of pentosan polysulfate sodium (PPS) with doses two to three times higher. METHODS: We evaluated three dosages (300, 600, and 900 mg) of PPS in a randomized, double-blind, double-dummy, parallel-group, multicenter, 32-week study. Adults (n = 380) with a diagnosis of interstitial cystitis (IC) as determined by a positive cystoscopic examination combined with bladder pain and urgency or a history of IC symptoms for at least 6 months were enrolled. Participants completed the Patient's Overall Rating of Symptom Index (PORIS) and the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI) at baseline (ICSI only) and during follow-up visits at 4, 8, 12, 16, 24, and 32 weeks. RESULTS: Mean ICSI scores improved significantly during the 32 weeks for all dosages (baseline 11.2, 11.9, and 11.9 to endpoint 8.2, 8.1, 8.6 for 300, 600, and 900 mg, respectively; P <0.001) but the response to treatment was not dose dependent (no statistically significant difference in response among the three dosages). At baseline, 3.2%, 62.2%, and 34.6% reported mild, moderate, and severe symptoms, respectively, as assessed by the ICSI. At study end, 27.5%, 56.9%, and 15.7% reported mild, moderate, and severe symptoms, respectively. The PORIS scores improved within 4 weeks with 15.8% to 21.1% of all patients classified as responders (50% or greater improvement on PORIS). At 32 weeks, 49.6%, 49.6%, and 45.2% of all patients were responders at a dose of 300, 600, and 900 mg, respectively. Most adverse events were mild and resolved without intervention. CONCLUSIONS: For all three dosages of PPS, a clinically significant but similar response was demonstrated. The duration of therapy appears to be more important than the dosage.
OBJECTIVES: To test whether the presence of Tamm-Horsfall protein (THP) can limit the injury caused by low-molecular-weight (LMW) urinary cations using an in vivo rat bladder injury model. Previous studies have shown that normal urine contains LMW cations toxic to cultured bladder cells and that THP, a ubiquitous urinary glycoprotein, protects against this cytotoxic effect. THP may sequester and subsequently neutralize these toxic urinary cations. METHODS: A dialysis product of LMW (greater than 100 but less than 3500) was prepared from pooled 24-hour urine samples from healthy volunteers and evaluated for urothelial cell cytotoxicity. The LMW toxic factor (TF) was instilled into the bladders of Sprague-Dawley rats (n = 9) after recording the baseline urodynamic parameters, primarily nonvoiding contractions (NVCs). We also evaluated the ability of THP to block abnormal physiologic activity indicative of bladder injury caused by exposure to the TF (greater than 100 but less than 3500 molecular weight) by co-instillation of the TF with THP. RESULTS: The TF had a significant cytotoxic effect in cultured rat (P < 0.01) and human (P < 0.01) bladder epithelial cells. Rat bladder NVCs increased significantly over baseline contractility when potassium chloride was infused after TF (1.68 +/- 0.11 NVC/min; P < 0.0001) but not after infusion of THP plus TF (0.28 +/- 0.085 NVC/min). CONCLUSIONS: Normal urine contains a cationic factor that appears to increase urothelial permeability by injuring the mucosa, allowing potassium ions to penetrate the urothelium and depolarize underlying nerves and muscle. THP appears to neutralize the LMW fraction electrostatically and attenuate urothelial damage, resulting in suppression of potassium chloride-mediated bladder hyperactivity.
PURPOSE: If most patients with interstitial cystitis (IC) have epithelial leakage allowing urinary K to penetrate the interstitium and provoke symptoms, urinary K should be lower in untreated patients than in healthy subjects and it should increase with successful heparinoid treatment. This study tested these hypotheses. MATERIALS AND METHODS: Na, K and creatinine (Cr) were determined in spot urine samples from new, symptomatic, untreated patients with IC meeting all National Institute of Diabetes and Digestive and Kidney Diseases clinical diagnostic criteria, returning patients with IC reporting 50% or greater symptom improvement after 4 or greater months of oral heparinoid therapy and control subjects, and in 24-hour urine samples from new untreated patients and controls. RESULTS: In spot urine specimens of 37 new patients with IC K-to-Cr ratios were significantly lower than in 18 controls (0.51 vs 0.88 mg/mg Cr, p = 0.001). A total of 50 successfully treated patients with IC had significantly higher K-to-Cr ratios than those in 37 new patients (0.66 vs 0.51 mg/mg Cr, p = 0.025). Na-to-Cr ratios in the 3 groups were not significantly different. In 24-hour urine specimens 30 new patients had lower average K (31.0 vs 46.2 mEq/l, p = 0.01) and lower K-to-Cr ratios (0.43 vs 0.52 mg K/mg Cr, p = 0.01) than in 47 controls, while Na was not significantly different. CONCLUSIONS: Our finding of lower urinary K in new, untreated patients supports the concept of abnormal epithelial permeability and K absorption in IC. Higher urinary K in successfully treated vs untreated patients may reflect decreasing urinary K absorption due to mucosal repair and a resulting decrease in epithelial permeability. K/mg Cr appears accurate for normalizing urinary K.
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OBJECTIVE: To determine whether men previously diagnosed with prostatitis also have pathology originating in the bladder. PATIENTS, SUBJECTS AND METHODS: We administered the pelvic pain and urgency/frequency (PUF) questionnaire and the potassium-sensitivity test (PST) to 50 patients with prostatitis presenting in urological and primary care, and to 14 controls. In a separate control group of 22 men, the urethra was irrigated with KCl or NaCl (11 each) before and after experimental injury of the urethral mucosa. RESULTS: All 50 patients with prostatitis had PUF scores of > or = 7; 77% were positive for the PST. All 14 controls had PUF scores of 1 or 0 and a negative PST. In the urethral irrigation study in controls, KCl but not NaCl provoked urethral pain after mucosal injury. Before injury, neither KCl nor NaCl caused symptoms. CONCLUSION: The high rate of positive PST in patients with "classic" prostatitis indicates that pathology originating in the bladder may be an important source of symptoms in most. In patients with prostatitis and female patients with interstitial cystitis, symptoms may arise not from separate disease entities but from a continuum of epithelial dysfunction and potassium cycling that may be present throughout the lower urinary tract.
Interstitial cystitis is more common than previously thought and is often diagnosed only when pain, frequency, and urgency become continuous and severe. Its diagnosis is straightforward, and effective therapies are available. Physicians should keep the diagnosis of interstitial cystitis in mind for all patients presenting with pelvic pain or urinary symptoms.
OBJECTIVES: Traditional epidemiologic studies have significantly underestimated interstitial cystitis (IC) prevalence because they surveyed populations for diagnosed cases rather than screening for IC symptoms and evaluating suspected cases. Our earlier data have suggested that IC affects almost 25% of women. To test this hypothesis, we used a validated IC symptom questionnaire and intravesical potassium sensitivity testing (PST), history, and physical examination to determine the prevalence of IC in a fixed population of young women. METHODS: All female members of the University of California, San Diego, third-year medical student class were asked to complete the Pelvic Pain and Urgency/Frequency (PUF) scale. All those scoring 7 or greater were asked to undergo clinical evaluation, including urinalysis, urine culture, and PST. RESULTS: Of 52 potential subjects, 49 (median age 26 years) completed the PUF scale. Of the 49, 15 (30.6%) scored 7 or greater; 5 of those 15 volunteered for PST. All 5 had negative urinalysis findings and were PST positive, for a 10% (5 of 52) rate of positive voluntary PST in the medical student population. All 15 subjects with PUF scores of 7 or greater reported being sexually active. Dyspareunia was present in 13 (87%) of the 15 women, including all 5 PST-positive subjects. CONCLUSIONS: We identified probable IC in 30.6% and documented IC in a minimum of 10% of the female medical students. These data suggest the estimate of IC prevalence in the United States should be vastly increased from approximately 1.5 million to perhaps 25 to 30 million women and that IC is highly prevalent in young women. Screening for IC-specific symptoms is a useful method for identifying undiagnosed IC cases.
PURPOSE: We identify early descriptions of interstitial cystitis and trace its evolution as a clinical entity during the 19th century. MATERIALS AND METHODS: Primary and secondary source documents relating to interstitial cystitis, bladder inflammation and bladder stones were reviewed. RESULTS: What is believed to be the earliest published record of interstitial cystitis appeared in an 1836 textbook by the Philadelphia surgeon Joseph Parrish, who documented a syndrome of chronic frequency, urgency, dysuria and pelvic pain he called "tic doloureux of the bladder." Tic doloureux was a contemporaneous diagnosis used to describe painful, idiopathic disorders of nerves. Parrish attributed this term to his mentor, Dr. Phillip Syng Physick, who applied it to patients with severe lower urinary tract symptoms with no discernible etiology, with the most common etiology during the 19th century being bladder stones. A review of archival material from the Philadelphia College of Physicians indicates that by 1808 Physick had developed a concept of bladder inflammation, a "bladder ulcer," that produced lower urinary tract symptoms in the absence of bladder stone. CONCLUSIONS: By 1808 Philip Syng Physick had described an inflammatory condition of the bladder producing the same lower urinary tract symptoms as a bladder stone. By 1836 he had expanded this concept to include a chronic frequency, urgency and pain syndrome occurring in the absence of demonstrable etiology. We propose that these are the earliest known descriptions of bladder inflammation and interstitial cystitis.
Interstitial cystitis is a relatively common disorder that can be treated successfully in the majority of cases. Symptoms can be effectively controlled, and disease pathophysiology addressed, using a multimodal medical regimen based on heparinoid therapy. As appropriate to the individual patient, heparinoid therapy is supplemented by oral medications aimed at reversing neural upregulation and controlling any allergies. A new and promising adjunct to the multimodal regimen is an intravesical therapeutic solution that combines pentosan polysulfate or heparin with lidocaine and sodium bicarbonate. Preliminary results indicate this therapeutic solution provides immediate temporary relief of symptoms.
Recent data show that in the significant majority of gynecologic patients, chronic pelvic pain (CPP) has its origin in the bladder in the chronic disease process known as interstitial cystitis (IC). IC can produce pain that is perceived in any location or locations in the pelvis in any combination, with or without urinary frequency/urgency. Until recently, the diagnosis of IC was complicated by the variable clinical presentation of the disease and a lack of diagnostic tools. With recent advances in the understanding of the disease, IC's distinctive symptom complex has become well known, and new diagnostic tools are available. Gynecologists can now test CPP patients for the presence of IC using a simple questionnaire, the Pelvic Pain and Urgency/Frequency (PUF) Patient Symptom Scale, and a minimally invasive, office-based procedure, the potassium sensitivity test (PST). Along with a careful history attuned to the characteristic clinical presentation of IC, the PUF Scale and PST can help the gynecologist establish the diagnosis and offer appropriate treatment promptly. IC can be treated very successfully in the majority of cases.
Gynecologists have been challenged by the diversity in treatment approaches and the historical absence of effective therapy for interstitial cystisis (IC). Until recently, the only Food and Drug Administration (FDA)-approved treatment was bladder instillation with dimethyl sulfoxide, a moderately effective and safe, albeit invasive, process. The approval in 1996 of pentosan polysulfate sodium (PPS) provided IC patients with an effective and safe oral regimen that specifically targets and repairs the damaged urothelium. Intravesical administration of heparin sulfate or PPS, while not FDA indicated, has also been shown to provide symptom relief. Patients with moderate to severe disease may require a multimodal therapeutic approach utilizing PPS as the foundation. Oral PPS can be combined with antihistamines, analgesics, antispasmodics or antidepressants to provide enhanced pain and symptom relief. Patients with severe disease or flares may benefit from instillation of an anesthetic therapeutic relief solution composed of heparin or PPS combined with sodium bicarbonate and lidocaine. Nonpharmacologic approaches, such as bladder training, biofeedback and dietary changes, can provide supplemental relief. Acute and chronic pain associated with IC can now be effectively managed using a multimodal approach with PPS as the basis.