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1.
Effects of veverimer on serum bicarbonate and physical function in women with chronic kidney disease and metabolic acidosis: a subgroup analysis from a randomised, controlled trial.
Mathur, VS, Wesson, DE, Tangri, N, Li, E, Bushinsky, DA
BMC nephrology. 2022;(1):82
Abstract
BACKGROUND Globally, the prevalence of chronic kidney disease (CKD) is higher in women than in men; however, women have been historically under-represented in nephrology clinical trials. Metabolic acidosis increases risk of progressive loss of kidney function, causes bone demineralization and muscle protein catabolism, and may be more consequential in women given their lower bone and muscle mass. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. METHODS This was a Phase 3, multicenter, randomised, blinded, placebo-controlled trial in 196 patients with CKD (eGFR: 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. We present the findings from a pre-specified subgroup analysis evaluating the effects of veverimer on metabolic acidosis and physical function among women (N = 77) enrolled in this trial. RESULTS At week 52, women treated with veverimer had a greater increase in mean (± standard error) serum bicarbonate than the placebo group (5.4 [0.5] vs. 2.2 [0.6] mmol/L; P < 0.0001). Physical Function reported by patients on the Kidney Disease and Quality of Life - Physical Function Domain, a measure that includes items related to walking, stair climbing, carrying groceries and other activities improved significantly in women randomized to veverimer vs placebo (+ 13.2 vs. -5.2, respectively, P < 0.0031). Objectively measured performance time on the repeated chair stand test also improved significantly in the veverimer group vs. placebo (P = 0.0002). CONCLUSIONS Veverimer was effective in treating metabolic acidosis in women with CKD, and significantly improved how they felt and functioned. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03390842 . Registered on January 4, 2018.
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Phase I dose escalation and pharmacokinetic study on the nanoparticle formulation of polymeric micellar paclitaxel for injection in patients with advanced solid malignancies.
Shi, M, Sun, J, Zhou, J, Yu, H, Yu, S, Xia, G, Wang, L, Teng, Y, Liu, G, Yu, C, et al
Investigational new drugs. 2018;(2):269-277
Abstract
Background Polymeric micellar paclitaxel (PM-paclitaxel) is a novel Cremophor EL-free, nanoparticle-encapsulated paclitaxel formulation administered through intravenous injection. The primary objective of this phase I trial was to determine the first cycle dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PM-paclitaxel. Secondary objectives included the evaluation of the safety, antitumor activity, and pharmacokinetic (PK) profile of PM-paclitaxel in patients with advanced malignancies. Methods The PM-paclitaxel dose was escalated from 175 mg/m2 (level 1) to 435 mg/m2 (level 5). PM-paclitaxel was intravenously administered to patients for 3 h without premedication on day 1 of a 21-day cycle. Results Eighteen patients with confirmed advanced malignancies received PM-paclitaxel. DLT included grade 4 neutropenia (four patients) and grade 3 numbness (one patient), which occurred in one of the six patients who received 300 mg/m2 (level 3) PM-paclitaxel and all three patients who were treated with 435 mg/m2 PM-paclitaxel. Thus, the MTD of PM-paclitaxel was determined as 390 mg/m2 (level 4). Acute hypersensitive reactions were not observed. Partial response was observed in six of 18 patients (33.3%), three of whom had prior exposure to paclitaxel chemotherapy. The peak concentration and area under the curve values of paclitaxel increased with increasing dosage, indicating that PM-paclitaxel exhibits linear PKs. Conclusions PM-paclitaxel showed high MTD without additional toxicity, and exhibited desirable antitumor activity. The recommended dose of PM paclitaxel for phase II study is 300 mg/m2.
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Treatment with patiromer decreases aldosterone in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors.
Weir, MR, Bakris, GL, Gross, C, Mayo, MR, Garza, D, Stasiv, Y, Yuan, J, Berman, L, Williams, GH
Kidney international. 2016;(3):696-704
Abstract
Elevated serum aldosterone can be vasculotoxic and facilitate cardiorenal damage. Renin-angiotensin system inhibitors reduce serum aldosterone levels and/or block its effects but can cause hyperkalemia. Patiromer, a nonabsorbed potassium binder, decreases serum potassium in patients with chronic kidney disease on renin-angiotensin system inhibitors. Here we examined the effect of patiromer treatment on serum aldosterone, blood pressure, and albuminuria in patients with chronic kidney disease on renin-angiotensin system inhibitors with hyperkalemia (serum potassium 5.1-6.5 mEq/l). We analyzed data from the phase 3 OPAL-HK study (4-week initial treatment phase of 243 patients; 8-week randomized withdrawal phase of 107 patients). In the treatment phase, the (mean ± standard error) serum potassium was decreased concordantly with the serum aldosterone (-1.99 ± 0.51 ng/dl), systolic/diastolic blood pressure (-5.64 ± 1.04 mm Hg/-3.84 ± 0.69 mm Hg), and albumin-to-creatinine ratio (-203.7 ± 54.7 mg/g), all in a statistically significant manner. The change in the plasma renin activity (-0.44 ± 0.63 μg/l/hr) was not significant. In the withdrawal phase, mean aldosterone levels were sustained with patiromer (+0.23 ± 1.07 ng/dl) and significantly increased with placebo (+2.78 ± 1.25 ng/dl). Patients on patiromer had significant reductions in mean systolic/diastolic blood pressure (-6.70 ± 1.59/-2.15 ± 1.06 mm Hg), whereas those on placebo did not (-1.21 ± 1.89 mm Hg/+1.72 ± 1.26 mm Hg). Significant changes in plasma renin activity were found only in the placebo group (-3.90 ± 1.41 μg/l/hr). Thus, patiromer reduced serum potassium and aldosterone levels independent of plasma renin activity in patients with chronic kidney disease and hyperkalemia on renin-angiotensin system inhibitors.
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A phase I dose escalation study of NK012, an SN-38 incorporating macromolecular polymeric micelle.
Burris, HA, Infante, JR, Anthony Greco, F, Thompson, DS, Barton, JH, Bendell, JC, Nambu, Y, Watanabe, N, Jones, SF
Cancer chemotherapy and pharmacology. 2016;(5):1079-86
Abstract
PURPOSE This study evaluated the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) and recommended phase II dose (RD) of NK012, a macromolecular polymeric micelle formulation of SN-38 (the active metabolite of irinotecan). PATIENTS AND METHODS Patients with previously treated advanced solid tumors and acceptable organ function were administered NK012 as a 30-min infusion every 21 or 28 days without premedications. Patients were screened for UGT1A1 *28 polymorphism prior to enrollment. Patients homozygous for UGT1A1*28 allele (*28/*28 genotype patients) were treated at a reduced dose level with the potential for dose escalation based on toxicities. Pharmacokinetic samples were obtained during cycles 1 and 2. RESULTS Thirty-nine patients were enrolled, and thirty-eight patients were treated with NK012. NK012 was escalated from 9 to 37 mg/m(2) in patients with UGT1A1*28 allele genotype of wt/wt and wt/*28. The MTD/RD of a Q21D regimen was determined to be 28 mg/m(2) where the dose-limiting toxicity is myelosuppression, which appears to be cumulative and limits timely subsequent dosing. Based on delayed neutrophil recovery, the NK012 dose of 28 mg/m(2) administered on an every 28 days schedule was confirmed as the RD. Gastrointestinal toxicities were mild, with no grade 3 diarrhea reported. The T1/2z value of polymer-unbound SN-38 was significantly prolonged compared to that of SN-38 metabolized from CPT-11, indicating a sustained high systemic SN-38 concentration. Six patients had confirmed partial responses. Eighteen additional patients had stable disease as their best response to treatment. CONCLUSIONS The recommended phase II dose of NK012 for UGT1A1 wt/wt and wt/*28 genotype patients is 28 mg/m(2) every 28 days. Additional clinical development as a single agent in specific patient populations or in combination with other chemotherapy agents is warranted.
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Reprocessing high-flux polysulfone dialyzers does not negatively impact solute removal in short-daily online hemodiafiltration.
Melo, NC, Moyses, RM, Elias, RM, Castro, MC
Hemodialysis international. International Symposium on Home Hemodialysis. 2014;(2):473-80
Abstract
There are no studies evaluating the impact of dialyzer reprocessing on solute removal in short-daily online hemodiafiltration (OL-HDF). Our aim was to evaluate the impact of dialyzer reuse on solute removal in daily OL-HDF and compare with that in high-flux short-daily hemodialysis (SDH). Fourteen patients undergoing a SDH program were included. Pre-dialysis and post-dialysis blood samples and effluent dialysate were collected in the 1st, 7th, and 13th dialyzer uses in SDH sessions and in daily OL-HDF sessions. Directly quantified small solute (urea, phosphorus, creatinine, and uric acid) total mass removal (TM(DQ)) and clearance (K(DQ)) were similar when the 1st, 7th, and 13th dialyzer SDH uses were compared with the 1st, 7th, and 13th daily OL-HDF uses. TMDQ and K(DQ) of small solutes were similar among analyzed dialyzer uses in SDH sessions and in daily OL-HDF sessions. β2-Microglobulin TM(DQ) and K(DQ) were statistically higher in daily OL-HDF dialyzer uses than in the respective SDH uses. There was no difference in β2-microglobulin TM(DQ) and K(DQ) among dialyzer uses in daily OL-HDF sessions or in SDH sessions. In daily OL-HDF, albumin loss was significantly different among dialyzer uses (P < 0.001), being lower in the 7th and 13th dialyzer uses than in the first use. Dialyzer reprocessing did not impair solute extraction in daily OL-HDF. β2-Microglobulin removal was greater in daily OL-HDF than in SDH sessions, without significant differences in other solutes extraction. There was a significant reduction in intradialytic albumin loss with dialyzer reprocessing in daily OL-HDF sessions.
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A Phase 1 dose-ranging study examining the effects of a superabsorbent polymer (CLP) on fluid, sodium and potassium excretion in healthy subjects.
Henderson, LW, Dittrich, HC, Strickland, A, Blok, TM, Newman, R, Oliphant, T, Albrecht, D
BMC pharmacology & toxicology. 2014;:2
Abstract
BACKGROUND CLP is an orally administered, non-absorbed, superabsorbent polymer being developed to increase fecal excretion of sodium, potassium and water in patients with heart failure and end-stage renal disease. This study was conducted to evaluate the safety of CLP, and to explore dose-related effects on fecal weight, fecal and urine sodium and potassium excretion, and serum electrolyte concentrations. METHODS This Phase 1, open-label, dose-escalation study included 25 healthy volunteers, who were administered CLP orally immediately prior to four daily meals for 9 days at doses of 7.5, 15.0, and 25.0 g/day (n = 5/group). An additional dose group received 15.0 g/day CLP under fasting conditions, and an untreated cohort (n = 5) served as control. Twenty-four-hour fecal and urinary output was collected daily. Samples were weighed, and sodium, potassium, and other ion content in stool and urine were measured for each treatment group. Effects on serum cation concentrations, other standard laboratory values, and adverse events were also determined. RESULTS At doses below 25.0 g/day, CLP was well tolerated, with a low frequency of self-limiting gastrointestinal adverse events. CLP increased fecal weight and fecal sodium and potassium content in a dose-related manner. Concomitant dose-related decreases in urinary sodium and potassium were observed. All serum ion concentrations remained within normal limits. CONCLUSIONS In this study, oral CLP removed water, sodium and potassium from the body via the gastrointestinal tract in a dose related fashion. CLP could become useful for patients with fluid overload and compromised kidney function in conditions such as congestive heart failure, salt sensitive hypertension, chronic kidney disease and end stage renal disease. TRIAL REGISTRATION NCT01944007.
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A multicenter phase II randomized study of Cremophor-free polymeric nanoparticle formulation of paclitaxel in women with locally advanced and/or metastatic breast cancer after failure of anthracycline.
Ranade, AA, Bapsy, PP, Nag, S, Raghunadharao, D, Raina, V, Advani, SH, Patil, S, Maru, A, Gangadharan, VP, Goswami, C, et al
Asia-Pacific journal of clinical oncology. 2013;(2):176-81
Abstract
AIMS: Paclitaxel is extensively used in the treatment of advanced carcinomas of the breast, ovary and non-small cell lung cancer. In clinical use it is formulated in the non-ionic surfactant polyethoxylated castor oil (Cremophor) and dehydrated alcohol to enhance drug solubility. Cremophor adds to toxic effects of paclitaxel by producing or contributing to the well-described hypersensitivity reactions that commonly occur during its infusion, affecting a large number of patients. This randomized trial was conducted to evaluate efficacy and safety of novel nanoparticle-based paclitaxel in the treatment of patients with advanced breast cancer. METHOD Patients were randomized to receive either nanoparticle paclitaxel (NP) 300 mg/m(2) , (NP300) or NP220 mg/m(2) or Cremophor paclitaxel 175 mg/m(2) (CP 175). NP was administered as a 1-h infusion without premedication and CP as a 3-h infusion with premedication every 3 weeks. RESULTS In total, 194 patients who had been administered at least one dose were included for safety analysis and 170 patients who completed at least two cycles of therapy were analyzed for efficacy. NP showed an overall response rate (complete response + partial response) of 40% in the NP220 and NP300 arms as compared to 31% in the CP arm. The incidence of neutropenia (all grades) was lowest in the NP220 arm (39.4%) compared to the NP300 (55%) and CP arm (50%). CONCLUSION NP is well tolerated and can be safely administered without any premedication in comparison to conventional paclitaxel, which requires the use of premedication before administration. NP demonstrates promising efficacy with a favorable safety profile.
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A new formulation of tolevamer, a novel nonantibiotic polymer, is safe and well-tolerated in healthy volunteers: a randomized phase I trial.
Peppe, J, Porzio, A, Davidson, DM
British journal of clinical pharmacology. 2008;(1):102-9
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Abstract
AIMS: To evaluate the safety and tolerability of a new oral solution formulation of tolevamer potassium sodium, a nonantibiotic polymer that binds Clostridium difficile toxins A and B. METHODS This phase 1 randomized, double-blind, placebo-controlled study evaluated four doses of tolevamer potassium sodium in 40 healthy volunteers using a sequential dose escalation paradigm and doses of 6, 9, 12 and 15 g day(-1) for 9 days. Within each 10 patient cohort, eight patients received active treatment and two matching placebo. Placebo subjects were pooled to provide eight per arm. All subjects received three times daily dosing on days 2-8 as well as a loading dose (a single dose equal to the total daily dose) either on day 1 or day 9. RESULTS All 40 subjects completed the study per protocol. Treatment-emergent adverse events (TEAEs) were generally mild, transient, and resolved without sequelae. There were no serious AEs or deaths. There was no relationship detected between dose and the incidence of TEAEs, whether drug-related (all gastrointestinal disorders) or not. No clinically significant changes in laboratory parameters, including serum and urinary potassium concentrations, vital signs, and results of physical examination, were observed. A small but statistically significant reduction in 24 h urine potassium excretion was seen in the 15 g day(-1) dose group, and on day 10 in the 6 g day(-1) group. CONCLUSIONS Tolevamer oral solution administered for 9 days at total daily doses up to 15 g, with loading doses of up to 15 g, was generally safe and well-tolerated in healthy volunteers.
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Multicenter phase II trial of Genexol-PM, a Cremophor-free, polymeric micelle formulation of paclitaxel, in patients with metastatic breast cancer.
Lee, KS, Chung, HC, Im, SA, Park, YH, Kim, CS, Kim, SB, Rha, SY, Lee, MY, Ro, J
Breast cancer research and treatment. 2008;(2):241-50
Abstract
Genexol-PM is a novel Cremophor EL-free polymeric micelle formulation of paclitaxel. This single arm, multicenter phase II study was designed to evaluate the efficacy and safety of Genexol-PM in patients with histologically confirmed metastatic breast cancer (MBC). Forty-one women received Genexol-PM by intravenous infusion at 300 mg/m2 over 3 h every 3 weeks without premedication until disease progression or intolerability. A total of 331 chemotherapy cycles were administered, with a median of 8 cycles per patient (range, 1-16). Overall response rate was 58.5% (95% CI: 43.5-72.3) with 5 complete responses and 19 partial responses. Thirty-seven patients who received Genexol-PM as a first-line therapy for their metastatic disease showed a response rate of 59.5% (95% CI: 43.5-73.7), and two responses were reported in four patients treated in the second-line setting for their metastatic disease. The median time to progression (TTP) for all patients was 9.0 months (range, 1.0-17.0+ months). Grade 3 non-hematologic toxicities included sensory peripheral neuropathy (51.2%), and myalgia (2.4%). Eight patients (19.5%) experienced hypersensitivity reactions, with grade 3 in two patients. Hematologic toxicities were grade 3 and 4 neutropenia (51.2 and 17.1%, respectively), and grade 1 and 2 thrombocytopenia (22.0%). Notably, no febrile neutropenia was observed. Genexol-PM appears a promising new paclitaxel in view of significant efficacies. Further trials with different dosing schedules, durations of delivery, or in combination with other drugs are warranted.
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[Polioxidonium in comprehensive therapy of recurrent herpetic stomatitis in children with allergic diseases].
Kuznetsova, OIu, Maksimovskaia, LN, Balabolkin, II, Gorshenina, AP, Semenov, GV
Stomatologiia. 2008;(6):52-5
Abstract
In the study with participation of 96 children of 1-7 years age with recurrent herpetic stomatitis and allergic diseases therapeutic efficacy of Polioxidonium was investigated. Polioxidonium was used in combination with traditional methods and with He-Ne-laser irradiation. Local oral cavity immunity, indexes of cellular immunity (in the reaction of lymphocytes blast-transformation with phytohemagglutinin), indexes of humoral immunity (IgG and IgE) were studied, complement C(3)-component was determined. Polioxidonium in combination with traditional methods and with laser therapy for recurrent herpetic stomatitis treatment in children with allergic diseases influenced favourably upon clinical course of allergic diseases, let achieve stable remission, increased efficacy of their treatment, promoted immunological status and shorten the terms of medical rehabilitation.