Pentosan polysulfate and a pigmentary maculopathy: causation versus correlation?

INTRODUCTION: Interstitial cystitis (IC) is a chronic disease with urinary tract symptoms and pain. Pentosan polysulfate (PPS) is the only U.S. Food and Drug Administration approved oral medication for the treatment of IC pain and symptoms. Recently, articles described a pigmentary maculopathy in IC patients on long term PPS therapy. Currently, there is no definitive study directly linking PPS as the cause of the pigmentary maculopathy. The aim of this review is to evaluate if PPS is the causative factor of the pigmentary maculopathy or if PPS use is only associated with the pigmentary maculopathy. MATERIALS AND METHODS: A comprehensive review of peer reviewed journals using the search terms IC, maculopathy, mast cells, immune inflammatory components, Tamm-Horsfall protein, cations and tight junctions was performed to examine the pathophysiology and role of chronic inflammation in IC and known retinal maculopathies. RESULTS: Chronic inflammatory cells have been reported in age-related macular degeneration choroid blood vessels and in bladder submucosal and detrusor layers in IC patients. Studies in IC and maculopathies demonstrate a significant milieu of activated chronic inflammatory and immunologic responses that cause a more "leaky" epithelium and a subsequent cascade of inflammatory events that results in the pathological changes seen in these two conditions. CONCLUSIONS: After an analysis of the literature describing a pigmentary maculopathy in IC patients on long term PPS, a causal relationship does not appear to be present. An alternate model is proposed postulating that the causative factor for the pigmentary maculopathy is the underlying inflammatory state associated with IC and not PPS use.

Role of urinary cations in the etiology of interstitial cystitis: A multisite study.

OBJECTIVE: To determine whether patients with interstitial cystitis have elevated levels of toxic urinary cations, to identify and quantify these cationic metabolites, and to assess their cytotoxicity. METHODS: Isolation of cationic fraction was achieved by solid phase extraction using an Oasis MCX cartridge on urine specimens from interstitial cystitis patients and controls. C18 reverse phase high-performance liquid chromatography was used to profile cationic metabolites, and they were quantified by the area under the peaks and normalized to creatinine. Major cationic fraction peaks were identified by reverse phase high-performance liquid chromatography and liquid chromatography-mass spectrometry. HTB-4 urothelial cells were used to determine the cytotoxicity of cationic fraction and of individual metabolites. RESULTS: The reverse phase high-performance liquid chromatography analysis was carried out on cationic fraction metabolites isolated from urine samples of 70 interstitial cystitis patients and 34 controls. The mean for controls versus patients was 3.84 (standard error of the mean 0.20) versus 6.71 (0.37) mAU*min/µg creatinine, respectively (P = 0.0001). The cationic fraction cytotoxicity normalized to creatinine for controls versus patients in mean percentage was -7.79% (standard error of the mean 3.32%) versus 20.03% (standard error of the mean 2.75%; P < 0.0005). The major toxic cations were 1-methyladenosine, 1-methylguanine, N2 ,N2 -dimethylguanosine and L-tryptophan. CONCLUSIONS: These data confirm significant elevation of toxic cations in the urine of interstitial cystitis patients. These toxic cations likely represent a primary cause of interstitial cystitis, as they can injure the bladder mucus and initiate an epithelial leak.

Heparin and alkalinized lidocaine versus alkalinized lidocaine for treatment of interstitial cystitis symptoms.

INTRODUCTION: Interstitial cystitis (IC), sometimes referred to as IC/bladder pain syndrome, is a substantial health care problem. Once considered a rare, orphan disease, it is now believed to be relatively common. This pilot study was undertaken to determine if the combination of heparin and alkalinized lidocaine (heparin-lidocaine) was more efficacious than alkalinized lidocaine at relieving pain and urgency symptoms associated with IC and also capable of yielding higher lidocaine absorption. MATERIALS AND METHODS: A single blind study was conducted on 14 IC patients with a heparin-lidocaine combination versus alkalinized lidocaine instilled intravesically. In a separate study serum lidocaine levels for heparin-alkalinized lidocaine combination versus USP lidocaine only were determined by high performance liquid chromatography. RESULTS: Alkalinized lidocaine and heparin have been reported to provide relief from pain and urgency symptoms associated with IC. The heparin-lidocaine combination significantly reduced the % of bladder pain (38% versus 13%, p = 0.029) and urgency (42% versus 8% p = 0.003) compared to lidocaine. In addition the GAR was significantly better for the heparin-lidocaine combination at both 1 hr % improved (77% versus 50%, p = 0.04) and 24 hrs (57% versus 23%, p = 0.002) after study drug treatment. Serum lidocaine levels for the heparin-lidocaine combination were significantly higher compared to USP lidocaine (unalkalinized). The mean +/- SEM was 0.45 +/- 0.09 µg/mL and 0.20 +/- 0.05 µg/mL, respectively (p = 0.019). CONCLUSIONS: In this pilot study the heparin-lidocaine combination results in significantly better relief of IC symptoms compared to alkalinized lidocaine and the combination yields higher lidocaine absorption than USP lidocaine.

Time-dependent clearance can confound exposure-response analysis of therapeutic antibodies: A comprehensive review of the current literature.

Exposure-response (ER) analysis is used to optimize dose and dose regimens during clinical development. Characterization of relationships between drug exposure and efficacy or safety outcomes can be utilized to make dose adjustments that improve patient response. Therapeutic antibodies typically show predictable pharmacokinetics (PK) but can exhibit clearance that decreases over time due to treatment. Moreover, time-dependent changes in clearance are frequently associated with drug response, with larger decreases in clearance and increased exposure seen in patients who respond to treatment. This often confounds traditional ER analysis, as drug response influences exposure rather than the reverse. In this review, we survey published population PK analyses for reported time-dependent drug clearance effects across 158 therapeutic antibodies approved or in regulatory review. We describe the mechanisms by which time-dependent clearance can arise, and evaluate trends in frequency, magnitude, and time scale of changes in clearance with respect to indication, mechanistic interpretation of time-dependence, and PK modeling techniques employed. We discuss the modeling and simulation strategies commonly used to characterize time-dependent clearance, and examples where time-dependent clearance has impeded ER analysis. A case study using population model simulation was explored to interrogate the impact of time-dependent clearance on ER analysis and how it can lead to spurious conclusions. Overall, time-dependent clearance arises frequently among therapeutic antibodies and has spurred erroneous conclusions in ER analysis. Appropriate PK modeling techniques aid in identifying and characterizing temporal shifts in exposure that may impede accurate ER assessment and successful dose optimization.

Rationale and design of an implant procedure and pivotal study to evaluate safety and effectiveness of Medtronic's tibial neuromodulation device.

Percutaneous tibial neuromodulation is a medical guideline recommended therapy for treating symptoms of overactive bladder. Stimulation is delivered to the tibial nerve via a thin needle placed percutaneously for 30 min once a week for 12-weeks, and monthly thereafter. Studies have shown that this therapy can effectively relieve symptoms of overactive bladder; however, the frequent office visits present a barrier to patients and can impact therapy effectiveness. To mitigate the burden of frequent clinic visits, small implantable devices are being developed to deliver tibial neuromodulation. These devices are implanted during a single minimally invasive procedure and deliver stimulation intermittently, similar to percutaneous tibial neuromodulation. Here, we describe the implant procedure and design of a pivotal study evaluating the safety and effectiveness for an implantable tibial neuromodulation device. The Evaluation of Implantable Tibial Neuromodulation (TITAN 2) pivotal study is a prospective, multicenter, investigational device exemption study being conducted at up to 30 sites in the United States and enrolling subjects with symptoms of overactive bladder.

Alkalinized lidocaine and heparin provide immediate relief of pain and urgency in patients with interstitial cystitis.

INTRODUCTION: It has been reported in an open-label study that the combination of alkalinized lidocaine and heparin can immediately relieve the symptoms of urinary urgency, frequency, and pain associated with interstitial cystitis (IC). This combination has also been reported to relieve pain associated with sex in patients with IC. AIM: The aim of this study was to corroborate these findings in a multicenter setting. METHODS: The study design was a multicenter prospective, double-blind, crossover, placebo-controlled trial. Each participant met all of the clinical National Institute of Diabetes and Digestive and Kidney Diseases criteria (excluding cystoscopy) for IC. Each patient received drug and control, in random order, within 48 hours of enrolling in the study. MAIN OUTCOME MEASURES: The primary outcome measure was percent change in pain score (11-point analog pain scale) 12 hours after receiving the drug or control. Secondary measures were the global assessment response (GAR) of symptoms and 12-hour average urgency reduction determined from 11-point urgency scales. RESULTS: Eighteen (18) patients completed the trial. The average reduction of pain over 12 hours was 21% for control and 42% for active drug (P = 0.0363). GAR was 13% for control and 50% for drug (P = 0.0137). Average urgency reduction was 13% for control and 35% for drug (P = 0.0328). CONCLUSIONS: The combination of alkalinized lidocaine and heparin provides up to 12 hours of relief from urgency and pain associated with IC. This combination provides significant immediate relief of symptoms for patients with IC.

Population pharmacokinetics of zanidatamab, an anti-HER2 biparatopic antibody, in patients with advanced or metastatic cancer.

PURPOSE: To characterize the pharmacokinetics (PK) of zanidatamab including evaluation of the impact of intrinsic and extrinsic patient factors. To investigate alternative dosing regimens to improve caregiver convenience and reduce zanidatamab wastage. METHODS: Serum zanidatamab concentrations were obtained from 305 patients with advanced or metastatic breast cancer, gastroesophageal adenocarcinoma (GEA), biliary tract cancer, and other HER2-expressing cancers from four ongoing phase I and II clinical trials. Zanidatamab PK were described using population methods. The exposure of alternative dosing regimens and the impact of dose delay was estimated by model simulation. RESULTS: A two-compartment model with parallel linear and nonlinear clearance from the central compartment adequately described zanidatamab PK. At the recommended dose regimens of 20 mg/kg Q2W and 30 mg/kg Q3W, zanidatamab clearance was primarily linear at steady state. At steady state, 30 mg/kg Q3W zanidatamab returns within 10% of the steady state trough after 2 subsequent doses following either a 1-week or 2-week dose delay. Statistically significant covariates included in the final model were body weight, sex, albumin, GEA cancer type, baseline tumor size, and presence of post-baseline anti-drug antibodies, all of which resulted in less than 30% impact on exposure. Model simulation predicts weight-based and two-tiered flat dosing will result in similar exposure and variability. CONCLUSION: The identified significant covariates were not considered clinically meaningful. Both weight-based (30 mg/kg Q3W) and two-tiered flat dosing (1800/2400 mg Q3W, 70 kg threshold) strategies are expected to provide similar exposures of zanidatamab.

A multi-site study confirms abnormal glycosylation in the Tamm-Horsfall protein of patients with interstitial cystitis.

PURPOSE: We confirm the single site observation of decreased sialylation and abnormal glycosylation of Tamm-Horsfall protein in patients with interstitial cystitis compared to control subjects. MATERIALS AND METHODS: Urine samples from 41 controls and 48 patients with interstitial cystitis from a total of 5 North American sites were obtained in blinded fashion as to participant status. Tamm-Horsfall protein was isolated from urine samples by salt precipitation. Protein content was determined by size exclusion chromatography and normalized to creatinine. Sialic acid was quantified by 1,2-diamino-4,5-methylene dioxybenzene (Sigma®) high performance liquid chromatography with fluorescence detection. Neutral and amino sugars were determined by high pH anion exchange chromatography with pulsed amperometric detection. N-glycans were labeled with 2-aminobenzamide and profiled using high pH anion exchange chromatography with fluorescence detection. Samples were also analyzed by matrix assisted laser desorption/ionization-time of flight mass spectrometry. Permethylated N-glycans were analyzed in the mass-to-charge ratio range of 3,000 to 6,000. RESULTS: There was no difference in the protein-to-creatinine ratio of Tamm-Horsfall protein from patients with interstitial cystitis vs controls (49.12 vs 46.4 mg/gm, p = 0.26). Sialic acid content (67 vs 77 nmol/mg Tamm-Horsfall protein, p = 0.025) and total monosaccharide content (590.9 vs 680.6 nmol/mg Tamm-Horsfall protein, p = 0.003) were significantly decreased in patients with interstitial cystitis vs controls. Results were supported by 2-aminobenzamide N-glycan profiling and mass spectrometry, which showed a 45% decrease in a major tetra-sialylated peak (mass-to-charge ratio 4,590) in Tamm-Horsfall protein from patients with interstitial cystitis compared to controls. CONCLUSIONS: These multisite data validate that abnormal glycosylation of Tamm-Horsfall protein occurs in patients with interstitial cystitis and may have a role in interstitial cystitis causation.

Impact of drug and equipment preparation on pre-hospital emergency Anaesthesia (PHEA) procedural time, error rate and cognitive load.

BACKGROUND: We examined the effect of advanced preparation and organisation of equipment and drugs for Pre-hospital Emergency Anaesthesia (PHEA) and tracheal intubation on procedural time, error rates, and cognitive load. METHODS: This study was a randomised, controlled experiment with a crossover design. Clinical teams (physician and paramedic) from the Emergency Medical Retrieval Service and the Scottish Air Ambulance Division were randomised to perform a standardised pre-hospital clinical simulation using either unprepared (standard practice) or pre-prepared (experimental method) PHEA equipment and drugs. Following a two-week washout period, each team performed the corresponding simulation. The primary outcome was intervention time. Secondary outcomes were safety-related incidents and errors, and degree of cognitive load. RESULTS: In total 23 experiments were completed, 12 using experimental method and 11 using standard practice. Time required to perform PHEA using the experimental method was significantly shorter than with standard practice (11,45 versus 20:59) minutes: seconds; p = < 0.001). The experimental method also significantly reduced procedural errors (0 versus 9, p = 0.007) and the cognitive load experienced by the intubator assistant (41.9 versus 68.7 mm, p = 0.006). CONCLUSIONS: Pre-preparation of PHEA equipment and drugs resulted in safer performance of PHEA and has the potential to reduce on-scene time by up to a third.

Defective Tamm-Horsfall protein in patients with interstitial cystitis.

PURPOSE: Normal urinary Tamm-Horsfall protein shows a urothelial cytoprotective effect against potentially toxic compounds in urine that may injure the urothelium and cause bladder disease. One such disease is interstitial cystitis. In patients with interstitial cystitis this protective effect is decreased. We hypothesized that a difference in Tamm-Horsfall protein in patients with interstitial cystitis exists that may be involved in disease pathogenesis. MATERIALS AND METHODS: Using enzyme-linked immunosorbent assay the urinary Tamm-Horsfall protein concentration was determined in patients with interstitial cystitis and control subjects. Sialic acid content was measured by high performance liquid chromatography based assay. The structure of the protein glycosylation chains was analyzed using matrix assisted laser desorption/ionization-time of flight mass spectrometry. RESULTS: The mean Tamm-Horsfall protein concentration was not significantly different in patients with interstitial cystitis and controls (28.8 vs 28.2 mg/l urine and 36.8 vs 36.7 microg/mg creatinine, respectively, p = 0.6). The total mean sialic acid content of Tamm-Horsfall protein was almost 2-fold lower in 22 patients with interstitial cystitis compared with that in 20 controls (46.3 +/- 4.3 vs 75.3 +/- 4.1 nmol sialic acid per mg Tamm-Horsfall protein, respectively, p <0.0001). On matrix assisted laser desorption/ionization-time of flight mass spectrometry N-glycans released from Tamm-Horsfall protein revealed lower molecular weight di-antennary N-glycan structures and a resulting decrease in the number of terminal sialic acid residues in 10 patients with interstitial cystitis relative to those in 10 controls. CONCLUSIONS: Tamm-Horsfall protein is qualitatively different in patients with interstitial cystitis compared to controls. These data suggest that altered Tamm-Horsfall protein may be involved in interstitial cystitis pathogenesis and it may be useful for clinical diagnosis.