A pilot trial of intravenous pamidronate for chronic low back pain.

Intravenous (i.v.) bisphosphonates relieve pain in conditions such as Paget's disease of bone, metastatic bone disease, and multiple myeloma. Based on positive findings from a prior case series, we conducted a randomized placebo-controlled study to assess the analgesic effect of i.v. pamidronate in subjects with chronic low back pain (CLBP) and evidence of degenerative disease of the spine. Four groups of 11 subjects (7 active, 4 placebo) were enrolled at escalating dose levels of 30, 60, 90, and 180 mg pamidronate (the latter administered as two 90 mg infusions). Primary outcomes were safety and change from baseline in average daily pain scores, recorded at 1, 2, 3, and 6 months postinfusion using electronic diaries. Secondary outcomes included responder rate, daily worst pain, and pain-related interference with daily function. There were no pamidronate-related serious adverse events or other significant safety findings. A statistically significant overall treatment difference in pain scores was observed, with clinically meaningful effects persisting for 6 months in the 180 mg pamidronate group. Least squares mean changes in daily average pain score were -1.39 (SE=0.43) for placebo, and -1.53 (0.71), -1.26 (0.81), -1.42 (0.65), and -4.13 (0.65) for pamidronate 30, 60, 90, and 180 mg, respectively (P=0.012 for pamidronate 180 mg vs placebo). The proportion of responders, changes in worst pain, and pain interference with daily function were also significantly improved for pamidronate 180 mg compared with placebo. In conclusion, i.v. pamidronate, administered as two 90 mg infusions, decreased pain intensity for 6 months in subjects with CLBP.

Pharmacological effects of CS-0777, a selective sphingosine 1-phosphate receptor-1 modulator: results from a 12-week, open-label pilot study in multiple sclerosis patients.

CS-0777 is a selective sphingosine 1-phosphate receptor-1 modulator under investigation for treatment of multiple sclerosis (MS). We conducted an open-label, pilot study in 25 MS patients to assess the safety, pharmacokinetics, pharmacodynamics and exploratory efficacy of oral CS-0777 (0.1, 0.3 and 0.6 mg), administered once weekly or every other week for 12 weeks. CS-0777 resulted in a pronounced, dose-dependent decrease in lymphocytes and CD4 T cell subsets, which returned to baseline within 4 weeks after the last dose. Overall, CS-0777 was safe and well-tolerated. These results require confirmation in a double-blind, placebo-controlled and adequately powered phase 2 study in MS.

Pharmacological modulation of peripheral T and B lymphocytes by a selective sphingosine 1-phosphate receptor-1 modulator.

CS-0777 is a selective sphingosine 1-phosphate receptor-1 (S1P(1)) modulator under development for treatment of autoimmune conditions. A randomized, double-blind, placebo-controlled study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CS-0777 in escalating dose cohorts of healthy male participants (0.1, 0.3, 1.0, and 2.5 mg; 6 active, 2 placebo per cohort). Primary pharmacodynamic parameters were absolute lymphocyte counts and lymphocyte subsets (CD4 and CD8 T and B cells). CS-0777 resulted in a pronounced, dose-dependent decrease in absolute lymphocyte counts (mean percent decrease from baseline at 24 hours postdose: 7%, 26%, 52%, 79%, and 85%, for placebo and 0.1, 0.3, 1.0, and 2.5 mg, respectively). Dose-related decreases of similar magnitude were observed for T and B cell subsets. Mean total white blood cell and neutrophil counts remained within normal ranges for all dose levels. CS-0777 was well tolerated, and there were no serious or severe adverse events. Mild, asymptomatic bradycardia and transaminase elevations (<3-fold upper limit of normal), similar to findings for other S1P receptor modulators, were observed at the highest dose level (2.5 mg). Therefore, CS-0777 shows potent activity in humans and may hold potential for treatment of autoimmune conditions such as multiple sclerosis.

Use of an exposure-response model to aid early drug development of an oral sphingosine 1-phosphate receptor modulator.

Pharmacokinetic (PK) and exposure-response modeling of a selective sphingosine 1-phosphate receptor-1 modulator (CS-0777) was conducted in an iterative process to guide early clinical development decisions. A model based on preclinical data from monkeys was extrapolated to humans to support a single ascending dose (SAD) study. The model was updated after each cohort, providing guidance on both maximal inhibition and time to recovery for lymphocyte counts. A 2-compartment PK model with first-order absorption and elimination was found to describe the monkey and human datasets. The relationship between lymphocyte counts and active metabolite (M-1) concentrations was modeled via an indirect response model, whereby M-1 inhibited the reentry of lymphocytes to the circulation. The indirect-response model based on SAD data had an Imax of approximately 85% and an IC50 of 0.24 ng/mL. Additionally, based on SAD data, similar models were developed for lymphocyte subsets, including CD4 cells. Subsequently, simulations were utilized to design a multiple ascending dose study with adaptive dosing regimens that would meet targeted pharmacodynamic (PD) response thresholds (eg, minimum 40% reduction in lymphocytes) while maintaining CD4 counts above a reasonable safety threshold. In conclusion, model-based development and use of adaptive designs for dose optimization can reduce the time and number of subjects needed in early clinical development.

Pain relief model for a COX-2 inhibitor in patients with postoperative dental pain.

AIM: To develop a pain relief model for a cyclooxygenase (COX)-2 inhibitor, CS-706, that permits prediction of doses for acute pain relief in Japanese and Western populations. METHODS: A categorical response model was developed to describe the probability of pain relief (PR) over time for a Phase 2a study. Models were also developed to describe patient's use of rescue medication and onset of pain relief. RESULTS: The placebo response was described by a first-order increase in PR that achieved a stable response after 4 h. The effect of CS-706 on PR was described using an E(max) model; the plasma concentration of CS-706 producing 50% of the maximum response was estimated to be 87 ng ml(-1), the median peak plasma concentration achieved after a 50-mg oral dose. The probability of rescue medication (REMD) decreased over time and was a function of the last observed PR score. This probability was < 16% for patients with a PR score > or =2. The probability of experiencing meaningful PR was 98% in patients who did not require REMD and 47% in those who required REMD. For patients who did not require REMD, the median onset time of meaningful pain relief (TMPR) decreased with increasing doses. In patients who required REMD, there was a saturable decline in TMPR, with the greatest improvement occurring from placebo to 50-mg doses. CONCLUSIONS: The set of models developed permitted compilation of multiple dose-response curves for dose selection of CS-706 in Westerners and facilitated scaling of doses to a Japanese population.

A randomized, double-blind, celecoxib- and placebo-controlled study of the effectiveness of CS-706 in acute postoperative dental pain.

BACKGROUND: CS-706 is a cyclooxygenase-2 (COX-2)-selective inhibitor with an in vitro selectivity ratio (COX-1:COX-2) similar to that of celecoxib. It has exhibited analgesic, anti-inflammatory, and antitumor properties in animal models. OBJECTIVES: This study evaluated the tolerability of single doses of CS-706 and compared the analgesic efficacy of CS-706 with that of celecoxib and placebo in the dental pain model. METHODS: This was a randomized, double-blind, double-dummy, active- and placebo-controlled study. Healthy male and female subjects with moderate to severe pain intensity (PI) after dental surgery were randomized ( approximately 50 per group) to receive a single oral dose of CS-706 10, 50, 100, or 200 mg; celecoxib 400 mg; or placebo. PI and pain relief (PR) were measured on categorical and visual analog scales through 24 hours after the dose. The primary efficacy variable was the time-weighted sum of PR scores at 4 hours after the dose (TOPAR4). The onset of analgesia was assessed by calculating the pain intensity difference (PID). Perceptible and meaningful pain relief were assessed using a 2-stopwatch method. RESULTS: The majority of subjects were female (62.0%) and white (59.5%). Subjects' mean (SD) age was 22.6 (3.9) years, and their mean body mass index was 25.3 (5.1) kg/m(2). All doses of CS-706 were associated with significant analgesic efficacy compared with placebo based on the primary end point, TOPAR4 (P<0.001), and on all secondary end points (P<0.05, comparisons of all CS-706 doses vs placebo) with the exception of time to 100% PR for CS-706 10 mg. Single 50-, 100-, and 200-mg doses of CS-706 also were significantly more effective than celecoxib for TOPAR4 (P=0.036, P=0.004, and P=0.006, respectively). The onset of analgesia (PID >or= 1) for all CS-706 doses occurred within 1 hour after dosing (P<0.001 vs placebo). The median duration of analgesia, measured as the time to administration of rescue medication, was significantly greater for all doses of CS-706 compared with placebo (5.7 hours for CS-706 10 mg, >24 hours for CS-706 50, 100, and 200 mg, and 1.7 hours for placebo; P<0.001 for CS-706 50, 100, and 200 mg). These data suggest that once-daily administration of CS-706 may be effective in providing relief of acute pain. The incidence of adverse events was similar among all treatment groups. Adverse events occurring in >or= 5 % of subjects in any treatment group were nausea, vomiting, dry socket, dizziness, headache, and paresthesia. CONCLUSION: Single doses of CS-706 had significant analgesic efficacy compared with celecoxib and placebo in the relief of postoperative dental pain in the healthy subjects enrolled in this study.

A randomized, double-blind, one-week study comparing effects of a novel COX-2 inhibitor and naproxen on the gastric mucosa.

CS-706 is a novel cyclooxygenase-2 (COX-2) inhibitor with potent analgesic, anti-inflammatory, and antitumor properties in animal models. This one-week, multicenter study was undertaken to assess the safety and tolerability of CS-706 and to compare the effects of CS-706 versus naproxen on acute gastrointestinal (GI) mucosal injury. Healthy men and women (n=160) without evidence of underlying gastroduodenal lesions were randomized to placebo, 100 mg CS-706 once daily, 200 mg CS-706 once daily, or 500 mg naproxen twice daily, administered for 7 days. On Day 8, subjects underwent a posttreatment upper GI endoscopy to assess development of gastroduodenal petechiae, erosions, and ulcers. Inhibition of COX-1 and COX-2 activity over the 24-hr postdose interval on Day 7 was determined in 48 subjects (12 per treatment group). CS-706 was safe and well tolerated. The extent of upper GI mucosal injury for both CS-706 dose groups was statistically significantly less than that for naproxen (P < 0.001) and was similar to placebo (P=0.615 and P=0.115 for 100 and 200 mg CS-706, respectively). No subject in placebo or either CS-706 treatment group had gastroduodenal ulcers, compared with 11 (28.2%) subjects treated with naproxen (P < 0.001). Both doses of CS-706 inhibited COX-2 activity to a similar extent as naproxen, whereas neither dose of CS-706 showed meaningful inhibition of platelet COX-1. In contrast, naproxen nearly completely inhibited COX-1 over the dosing interval. We conclude that CS-706, dosed up to 200 mg once daily, has an acute, upper GI toxicity profile similar to that of placebo and significantly superior to that of naproxen.

Dialysis modalities and dyslipidemia.

Progressive renal failure is accompanied by dyslipidemia, which is reflected in an abnormal apolipoprotein profile. It is characterized by increased concentrations of intact and partially metabolized triglyceride-rich apoB-containing lipoproteins. They occur preferentially in very-low density lipoprotein (VLDL) and low-density lipoprotein (LDL) as a result of impaired metabolism and clearance. Hemodialysis can moderately attenuate the renal dyslipidemia. In contrast, peritoneal dialysis is associated with further aggravation, including an increase of cholesterol-rich apoB-containing lipoproteins.

Effects of intraperitoneal hyaluronan on peritoneal fluid and solute transport in peritoneal dialysis patients.

BACKGROUND: Hyaluronan (HA) is a glycosaminoglycan found in connective tissues and tissue spaces, including the peritoneal cavity. In vivo studies in a rat model of peritoneal dialysis (PD) have shown that addition of HA to PD solution during an intraperitoneal dwell can alter peritoneal fluid transport and protect the peritoneal membrane from the effects of inflammation and repeated infusions of dialysis solution. The current study sought to evaluate the safety of intraperitoneal HA and its effect on peritoneal fluid and solute transport when administered during a dialysis dwell in humans. METHODS: 13 PD patients were enrolled in a prospective, randomized crossover study involving three dialysis treatments using the following PD solutions: (1) a commercially available PD solution (Dianeal PD-4, 1.36% glucose; Baxter Healthcare Corporation, Alliston, Ontario, Canada); (2) Dianeal PD-4 containing 0.1 g/L HA, and (3) Dianeal PD-4 containing 0.5 g/L HA. Each 6-hour dialysis exchange was separated from the other exchanges by a 2-week washout period. Radioiodinated human serum albumin (RISA) was administered with the dialysis solution to evaluate intraperitoneal volume, net ultrafiltration (UF), and fluid reabsorption. Peritoneal clearances, dialysate/plasma ratios (D/P), and mass transfer area coefficients (MTACs) were determined for sodium, urea, creatinine, albumin, and glucose. Safety was evaluated by monitoring adverse events and changes in serum chemistries. Ten patients completed all three dialysis exchanges and two additional patients completed at least one treatment exchange. RESULTS: There were no reported adverse events related to HA administration and no significant changes in serum chemistries. There were no significant differences in net UF or peritoneal volume profiles among the three treatments. Mean net UF calculated using residual volumes, estimated by RISA dilution, tended to be slightly higher during treatment with solution containing 0.1 g/L HA and 0.5 g/L HA [74 +/- 86 (SE) and 41 +/- 99 mL, respectively] compared to control treatment (-58 +/- 129 mL). Although not statistically significant, there was a trend toward decreased fluid reabsorption during treatment with HA. Solute clearances, D/P ratios, and MTACs were similar for the three treatments. Serum levels of HA were also unaffected by the two treatment solutions. CONCLUSIONS: These data support the acute safety of HA when administered intraperitoneally with the dialysis solution to PD patients. Due to the small sample size and variability in net UF and fluid reabsorption, statistically significant differences were not demonstrated for these parameters. However, a trend toward decreased fluid reabsorption was observed, suggesting that HA may act by a mechanism similar to that observed in animal studies. Further studies are necessary to evaluate whether the beneficial effects of HA observed in animal studies can be shown in humans.

A rapid assay for icodextrin determination in plasma and dialysate.

Icodextrin is a glucose polymer osmotic agent used to achieve sustained ultrafiltration during long peritoneal dialysis dwells. Previous assays for icodextrin in plasma and dialysate samples involved laborious methods, such as gel permeation chromatography with post-column derivatization of the eluted glucose polymers. We developed and validated a simple and more rapid assay for icodextrin using amyloglucosidase to hydrolyze all glucose polymers to glucose. Glucose was determined pre- and post-hydrolysis using a glucose hexokinase assay, and icodextrin concentration was calculated as the difference between glucose levels before and after hydrolysis. The complete hydrolysis of icodextrin to glucose was confirmed using anion exchange chromatography. Recovery studies using icodextrin powder added to plasma or dialysate showed 100% +/- 15% recovery for plasma concentrations from 10 mg/dL to 800 mg/dL and for dialysate concentrations from 50 mg/dL to 800 mg/dL. The percent relative standard deviation (%RSD) based on multiple replicates was within 6%, except at plasma icodextrin concentrations of 10 mg/dL and below. This simple and reliable assay has been used routinely in our laboratory to analyze thousands of plasma and dialysate samples from patients using Extraneal peritoneal dialysis solution (Baxter Healthcare Corporation, Deerfield, IL, U.S.A.).

Kinetic analysis of icodextrin interference with serum amylase assays.

Patients treated with Extraneal peritoneal dialysis solution (Baxter Healthcare Corporation, Deerfield, IL, U.S.A.) have a significant decrease in serum amylase activity. The decline is reported to be due to interference of icodextrin in a routinely used laboratory assay. The present study was designed to investigate the kinetics of icodextrin interference in the amylase activity assay and to determine whether assay interference can account for the total decline in amylase activity. Plasma obtained from healthy volunteers was spiked with 0, 0.21, 0.71, and 3.6 mg/mL icodextrin. Amylase activity was determined using Sigma kit 577-10 (Sigma Diagnostics, St. Louis, MO, U.S.A.). Amylase activity in plasma samples spiked with 3.6 mg/mL icodextrin was also monitored while varying the concentration of the substrate (ET-G7-PNP) from the assay kit. Amylase activity decreased with increasing amounts of icodextrin and decreasing amounts of assay substrate. A 72.6% decrease in amylase activity was observed in samples spiked with 3.6 mg/mL icodextrin as compared with samples without icodextrin at a substrate level similar to that in the assay kit (0.71 mmol/L). Double reciprocal and Dixon plots indicate competitive inhibition of amylase activity by icodextrin. Icodextrin functions as a competitive inhibitor in the assay for amylase activity, as predicted by the structural similarities between icodextrin and the amylase assay substrate. The degree of icodextrin interference suggests that the entire decline in amylase activity observed in patients using Extraneal can be accounted for qualitatively by icodextrin interference. The amylase activity decline in patients treated with Extraneal is an artifact attributable to assay interference.

Pharmacokinetics of icodextrin in peritoneal dialysis patients.

UNLABELLED: Pharmacokinetics of icodextrin in peritoneal dialysis patients. BACKGROUND: Icodextrin is a glucose polymer osmotic agent used to provide sustained ultrafiltration during long peritoneal dialysis (PD) dwells. A number of studies have evaluated the steady-state blood concentrations of icodextrin during repeated use; however, to date the pharmacokinetics of icodextrin have not been well studied. The current study was conducted to determine the absorption, plasma kinetics and elimination of icodextrin and metabolites following a single icodextrin exchange. METHODS: Thirteen PD patients were administered 2.0 L of solution containing 7.5% icodextrin for a 12-hour dwell. Icodextrin (total of all glucose polymers) and specific polymers with degrees of polymerization ranging from two to seven (DP2 to DP7) were measured in blood, urine and dialysate during the dwell and after draining the solution from the peritoneal cavity. RESULTS: A median of 40.1% (60.24 g) of the total administered dose (150 g) was absorbed during the 12-hour dwell. Plasma levels of icodextrin and metabolites rose during the dwell and declined after drain, closely corresponding to the one-compartment pharmacokinetic model assuming zero-order absorption and first-order elimination. Peak plasma concentrations (median C peak = 2.23 g/L) were observed at the end of the dwell (median Tmax = 12.7 h) and were significantly correlated with patients' body weight (R2 = 0.805, P < 0.001). Plasma levels of icodextrin and metabolites returned to baseline within 3 to 7 days. Icodextrin had a plasma half-life of 14.73 hours and a median clearance of 1.09 L/h. Urinary excretion of icodextrin and metabolites was directly related to residual renal function (R2 = 0.679 vs. creatinine clearance, P < 0.01). In the nine patients with residual renal function, the average daily urinary excretion of icodextrin was 473 +/- 77 mg per mL of endogenous renal creatinine clearance. Icodextrin metabolites DP2 to DP4 were found in the dialysate of subsequent dextrose exchanges, contributing to their elimination from blood. Changes in intraperitoneal concentrations of icodextrin metabolites during the dwell revealed a dual pattern, with a progressive rise in the dialysate concentration of smaller polymers (DP2 to DP4) and a progressive decline in the dialysate concentrations of the larger polymers (DP5 to DP7), suggesting some intraperitoneal metabolism of the glucose polymers. This increase in dialysate metabolite levels, however, did not contribute significantly to dialysate osmolality. In addition, some diffusion of maltose (DP2) from blood to dialysate may have occurred. There were no changes in serum insulin or glucose levels during icodextrin administration, indicating that icodextrin does not result in hyperglycemia or hyperinsulinemia as occurs during dextrose-based dialysis. Serum sodium and chloride declined in parallel with the rise in plasma levels of icodextrin, supporting the hypothesis that these electrolyte changes are the result of the increased plasma osmolality due to the presence of icodextrin metabolites. CONCLUSIONS: The pharmacokinetics of icodextrin in blood following intraperitoneal administration conforms to a simple, single-compartment model that can be approximated by zero-order absorption and first-order elimination. A small amount of intraperitoneal metabolism of icodextrin occurs but does not contribute significantly to dialysate osmolality. The metabolism of absorbed icodextrin and the resultant rise in plasma levels of small glucose polymers (DP2 to DP4) do not result in hyperglycemia or hyperinsulinemia, but may result in a small decrease in serum sodium and chloride.

Alterations in lipoprotein composition in peritoneal dialysis patients.

OBJECTIVE: Dyslipidemia is common among patients with end-stage renal disease, whether treated by hemodialysis (HD) or peritoneal dialysis (PD). To better understand the specific lipoprotein abnormalities in PD patients, we measured the lipid and apolipoprotein (Apo) composition of the four major classes of plasma lipoproteins in PD patients, HD patients, and healthy control subjects: very low density (VLDL), intermediate density (IDL), low density (LDL), and high density lipoproteins (HDL). DESIGN: Fasting plasma samples were obtained from 15 nondiabetic PD patients, 15 nondiabetic HD patients, and 16 healthy control subjects, all from a cross section of patients and subjects in the region of Göteborg, Sweden. Lipoproteins were isolated by preparative ultracentrifugation, and lipid and apolipoprotein concentrations were measured by gas chromatography and electroimmunoassay, respectively. RESULTS: Alterations in lipoprotein composition were apparent in all four lipoprotein density classes from PD and HD patients. VLDL contained a significantly higher concentration of ApoCIII in both HD and PD patients, and an elevation of free cholesterol, triglyceride, ApoB, ApoCII, and ApoE in PD patients. IDL from both PD and HD patients contained an excess of free and esterified cholesterol and triglyceride and significantly elevated levels of ApoB, ApoCII, ApoCIII, and ApoE. LDL had a higher concentration of ApoB in PD patients and elevated triglyceride and ApoCIII in both PD and HD patients. HDL isolated from PD patients had lower free cholesterol and ApoAI levels compared to control subjects, but these were not significantly different from HD patients. CONCLUSIONS: An increase in lipid and apolipoprotein mass in IDL, and an enrichment of ApoCIII in VLDL, IDL, and LDL were observed in both HD and PD patients. The predominant alteration in lipoprotein composition distinguishing PD patients from HD patients was an elevation of ApoB in LDL. Further study of these alterations in lipoprotein composition in PD patients will be helpful in understanding the underlying causes of dyslipidemia and, ultimately, to the selection of hypolipidemic drugs or other treatments to reduce the cardiovascular risks associated with dyslipidemia in these patients.