Quality of life improvement in patients with hard-to-heal leg wounds treated with Prontosan wound irrigation solution and wound gel.

OBJECTIVE: This study evaluated the impact of four weeks of treatment with Prontosan Wound Irrigation Solution and Prontosan Wound Gel (B. Braun Medical Inc., US) on adults with hard-to-heal leg wounds. Overall change (weeks 1-5) in the Global Quality of Life scale (GQOL), changes in body, psyche and everyday life (EDL) quality of life (QoL) subscores, and changes in wound appearance and size after treatment were assessed. METHOD: In this prospective, open-label, single-arm, five-centre study, non-hospitalised patients with no more than two wounds below the knee were recruited into the study; wounds were ≥5cm2 and ≤50cm2 and present for ≥4 weeks. The investigator or a designee applied the wound solution and gel to the wounds at clinic visits, and patients/caregivers applied the wound solution and gel at home. Wound-QoL questionnaires were completed at the initial screening and at each week of treatment. Wound size and photographs were obtained at pre- and post-treatment during clinic visits. RESULTS: A total of 43 patients were enrolled in the study. Mean GQOL scores decreased by 1.11 (46.1%). Body, psyche and EDL decreased by 1.17 (60.0%), 1.26 (41.8%) and 1.00 (42.2%), respectively. Wounds also showed improvement in odour, appearance and size. Adverse events were mild in intensity and transient in nature. CONCLUSION: This study demonstrated marked improvement in the QoL of patients with hard-to-heal leg wounds below the knee during four weeks of treatment with the wound solution and gel. Wounds also showed improvement in odour, appearance and size, and the treatment solution and gel were well tolerated. DECLARATION OF INTEREST: B. Braun Medical Inc. funded the research and preparation of this article. AK, DV, CRC and WC are employees of B. Braun Medical Inc. AO and RS declare no conflict of interest.

Types and Frequency of Infusion Pump Alarms: Protocol for a Retrospective Data Analysis.

BACKGROUND: The variety of alarms from all types of medical devices has increased from 6 to 40 in the last three decades, with today's most critically ill patients experiencing as many as 45 alarms per hour. Alarm fatigue has been identified as a critical safety issue for clinical staff that can lead to potentially dangerous delays or nonresponse to actionable alarms, resulting in serious patient injury and death. To date, most research on medical device alarms has focused on the nonactionable alarms of physiological monitoring devices. While there have been some reports in the literature related to drug library alerts during the infusion pump programing sequence, research related to the types and frequencies of actionable infusion pump alarms remains largely unexplored. OBJECTIVE: The objectives of this study protocol are to establish baseline data related to the types and frequency of infusion pump alarms from the B. Braun Outlook 400ES Safety Infusion System with the accompanying DoseTrac Infusion Management Software. METHODS: The most recent consecutive 60-day period of backup hospital data received between April 2014 and February 2017 from 32 United States-based hospitals will be selected for analysis. Microsoft SQL Server (2012 - 11.0.5343.0 X64) will be used to manage the data with unique code written to sort data and perform descriptive analyses. A validated data management methodology will be utilized to clean and analyze the data. Data management procedures will include blinding, cleaning, and review of existing infusion data within the DoseTrac Infusion Management Software databases at each hospital. Patient-identifying data will be removed prior to merging into a dedicated and secure data repository. This pooled data will then be analyzed. RESULTS: This exploratory study will analyze the aggregate alarm data for each hospital by care area, drug infused, time of day, and day of week, including: overall infusion pump alarm frequency (number of alarms per active infusion), duration of alarms (average, range, median), and type and frequency of alarms distributed by care area. CONCLUSIONS: Infusion pump alarm data collected and analyzed in this study will be used to help establish a baseline of infusion pump alarm types and relative frequencies. Understanding the incidences and characteristics of infusion pump alarms will result in more informed quality improvement recommendations to decrease and/or modify infusion pump alarms, and potentially reduce clinical staff alarm fatigue and improve patient safety. . REGISTERED REPORT IDENTIFIER: RR1-10.2196/10446.

Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Canagliflozin in Healthy Chinese Subjects.

PURPOSE: Canagliflozin, an orally active sodium-glucose cotransporter 2 inhibitor, is approved in many countries as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The recommended dose of canagliflozin is 100 or 300 mg once daily. This Phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, and safety profile of canagliflozin in healthy Chinese subjects. METHODS: In this double-blind, single-dose, 3-way crossover study, 15 healthy subjects were randomized (1:1:1) to receive single oral doses of canagliflozin 100 mg, canagliflozin 300 mg, or placebo. Pharmacokinetic, pharmacodynamic, and safety assessments were made at prespecified time points. FINDINGS: All participants are healthy Chinese adults. Mean AUC and Cmax of canagliflozin increased in a dose-dependent manner after single-dose administration (AUC0-∞, 10,521 ng · h/mL for 100 mg, 33,583 ng · h/mL for 300 mg; Cmax, 1178 ng/mL for 100 mg, 4113 ng/mL for 300 mg). The mean apparent t½ and the median Tmax of canagliflozin were independent of dose (t½, 16.0 hours for 100 mg, 16.2 hours for 300 mg; Tmax, ~1 hour). Mean CL/F and renal clearance of canagliflozin were comparable between the 2 doses. Mean plasma metabolite to parent molar ratios for Cmax and AUC0-∞ were similar with both doses. Canagliflozin decreased the 24-hour mean renal threshold for glucose, calculated by using measured creatinine clearance to estimate the glomerular filtration rate (67.9 and 60.7 mg/dL for canagliflozin 100 and 300 mg, respectively) and 24-hour increased urinary glucose excretion (33.8 and 42.9 g for canagliflozin 100 and 300 mg, respectively) in a dose-dependent manner; the 24-hour plasma glucose profile remained largely unchanged. No deaths, hypoglycemic events, or discontinuations due to adverse events were observed. IMPLICATIONS: Pharmacokinetics (AUC and Cmax) of canagliflozin increased in a dose-dependent manner after single oral doses of canagliflozin (100 and 300 mg) in these healthy Chinese subjects. Tmax and t½ of canagliflozin were independent of the dose. Canagliflozin decreased the 24-hour mean renal threshold for glucose and increased urinary glucose excretion in a dose-dependent manner; these results are consistent with those observed in other patient populations. Canagliflozin was generally safe and well tolerated in these healthy Chinese subjects. ClinicalTrials.gov identifier: NCT01707316.

Pharmacokinetics and pharmacodynamics of once- and twice-daily multiple-doses of canagliflozin, a selective inhibitor of sodium glucose co-transporter 2, in healthy participants.

AIMS: Assess the steady-state pharmacokinetics, pharmacodynamics and safety of once-daily (q.d.) versus twice-daily (b.i.d.) dosing with canagliflozin at the same total daily doses of 100 and 300 mg in healthy participants. METHODS: 34 participants (17 in each cohort) were enrolled in this single-center, open-label, multiple-dose, 2-cohort, 2-way crossover study. Participants in each cohort received a total daily dose of either 100 or 300 mg canagliflozin for 5 days with q.d. then b.i.d. dosing or vice versa. Pharmacokinetics and pharmacodynamics were assessed on day 5 of each period. RESULTS: The canagliflozin Cmax,ss of 100 and 300 mg q.d. dosing were higher by 66% and 72% than corresponding morning Cmax,ss of the 50 mg and 150 mg b.i.d. regimen, respectively. The geometric mean ratios (90% CI) of b.i.d./q.d. for AUC0-24h,ss at total doses of 100 and 300 mg were 97.08 (94.08; 99.62) and 99.32 (94.71; 104.16) respectively. Median tmax and mean t1/2 were independent of dose and regimen. Mean (SE) 24-h mean renal glucose threshold values for b.i.d. and q.d. regimens were 59.2 (1.03) and 60.2 (1.03) mg/dL for the 100 mg daily doses and 51.0 (1.04) and 52.5 (1.04) mg/dL for the 300 mg daily doses. Mean (SE) values of 24-h urinary glucose excretion for b.i.d. and q.d. regimens were 52.8 (1.94) and 48.6 (1.94) g for the 100 mg daily doses and 58.6 (3.81) and 57.8 (3.81) g for the 300 mg daily doses. Both doses were safe and well tolerated. CONCLUSION: Pharmacokinetics and pharmacodynamics of canagliflozin administered q.d. relative to b.i.d. at the same 100 and 300 mg total daily doses were comparable. Overall, canagliflozin was well tolerated.

Effect of hepatic or renal impairment on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor.

PURPOSE: Canagliflozin is a sodium-glucose cotransporter 2 inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). Because T2DM is often associated with renal or hepatic impairment, understanding the effects of these comorbid conditions on the pharmacokinetics of canagliflozin, and further assessing its safety, in these special populations is essential. Two open-label studies evaluated the pharmacokinetics, pharmacodynamics (renal study only), and safety of canagliflozin in participants with hepatic or renal impairment. METHODS: Participants in the hepatic study (8 in each group) were categorized based on their Child-Pugh score (normal hepatic function, mild impairment [Child-Pugh score of 5 or 6], and moderate impairment [Child-Pugh score of 7-9]) and received a single oral dose of canagliflozin 300 mg. Participants in the renal study (8 in each group) were categorized based on their creatinine clearance (CLCR) (normal renal function [CLCR ≥80 mL/min]; mild [CLCR 50 to <80 mL/min], moderate [CLCR 30 to <50 mL/min], or severe [CLCR <30 mL/min] renal impairment; and end-stage renal disease [ESRD]) and received a single oral dose of canagliflozin 200 mg; the exception was those with ESRD, who received 1 dose postdialysis and 1 dose predialysis (10 days later). Canagliflozin's pharmacokinetics and pharmacodynamics (urinary glucose excretion [UGE] and renal threshold for glucose excretion [RTG]) were assessed at predetermined time points. FINDINGS: Mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinite (AUC)0-∞ values differed by <11% between the group with normal hepatic function and those with mild and moderate hepatic impairment. In the renal study, the mean Cmax values were 13%, 29%, and 29% higher and the mean AUC0-∞ values were 17%, 63%, and 50% higher in participants with mild, moderate, and severe renal impairment, respectively; values were similar in the ESRD group relative to the group with normal function, however. The amount of UGE declined as renal function decreased, whereas RTG was not suppressed to the same extent in the moderate to severe renal impairment groups (mean RTG, 93-97 mg/dL) compared with the mild impairment and normal function groups (mean RTG, 68-77 mg/dL). IMPLICATIONS: Canagliflozin's pharmacokinetics were not affected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin increased in the renal impairment groups relative to participants with normal renal function. Pharmacodynamic response to canagliflozin, measured by using UGE and RTG, declined with increasing severity of renal impairment. A single oral dose of canagliflozin was well tolerated by participants in both studies. ClinicalTrials.gov identifiers: NCT01186588 and NCT01759576.

Pharmacokinetic interactions between topiramate and pioglitazone and metformin.

OBJECTIVE: To investigate potential drug-drug interactions between topiramate and metformin and pioglitazone at steady state. METHODS: Two open-label studies were performed in healthy adult men and women. In Study 1, eligible participants were given metformin alone for 3 days (500 mg twice daily [BID]) followed by concomitant metformin and topiramate (titrated to 100mg BID) from days 4 to 10. In Study 2, eligible participants were randomly assigned to treatment with pioglitazone 30 mg once daily (QD) alone for 8 days followed by concomitant pioglitazone and topiramate (titrated to 96 mg BID) from days 9 to 22 (Group 1) or to topiramate (titrated to 96 mg BID) alone for 11 days followed by concomitant pioglitazone 30 mg QD and topiramate 96 mg BID from days 12 to 22 (Group 2). An analysis of variance was used to evaluate differences in pharmacokinetics with and without concomitant treatment; 90% confidence intervals (CI) for the ratio of the geometric least squares mean (LSM) estimates for maximum plasma concentration (Cmax), area under concentration-time curve for dosing interval (AUC12 or AUC24), and oral clearance (CL/F) with and without concomitant treatment were used to assess a drug interaction. RESULTS: A comparison to historical data suggested a modest increase in topiramate oral clearance when given concomitantly with metformin. Coadministration with topiramate reduced metformin oral clearance at steady state, resulting in a modest increase in systemic metformin exposure. Geometric LSM ratios and 90% CI for metformin CL/F and AUC12 were 80% (75%, 85%) and 125% (117%, 134%), respectively. Pioglitazone had no effect on topiramate pharmacokinetics at steady state. Concomitant topiramate resulted in decreased systemic exposure to pioglitazone and its active metabolites, with geometric LSM ratios and 90% CI for AUC24 of 85.0% (75.7%, 95.6%) for pioglitazone, 40.5% (36.8%, 44.6%) for M-III, and 83.8% (76.1%, 91.2%) for M-IV, respectively. This effect appeared more pronounced in women than in men. Coadministration of topiramate with metformin or pioglitazone was generally well tolerated by healthy participants in these studies. CONCLUSIONS: A modest increase in metformin exposure and decrease in topiramate exposure was observed at steady state following coadministration of metformin 500 mg BID and topiramate 100mg BID. The clinical significance of the observed interaction is unclear but is not likely to require a dose adjustment of either agent. Pioglitazone 30 mg QD did not affect the pharmacokinetics of topiramate at steady state, while coadministration of topiramate 96 mg BID with pioglitazone decreased steady-state systemic exposure to pioglitazone, M-III, and M-IV. While the clinical consequence of this interaction is unknown, careful attention should be given to the routine monitoring for adequate glycemic control of patients receiving this concomitant therapy. Concomitant administration of topiramate with metformin or pioglitazone was generally well tolerated and no new safety concerns were observed.

Pharmacokinetics of topiramate in patients with renal impairment, end-stage renal disease undergoing hemodialysis, or hepatic impairment.

PURPOSE: Topiramate is primarily renally excreted. Chronic renal and hepatic impairment can affect the clearance of topiramate. Therefore, the objective was to establish dosage guidelines for topiramate in chronic renal impairment, end-stage renal disease (ESRD) undergoing hemodialysis, or chronic hepatic impairment patients. METHODS: In 3 separate open-label, parallel group studies (n=5-7/group), in patients with mild-moderate and severe renal impairment (based on creatinine clearance), ESRD requiring hemodialysis, or moderate-severe hepatic impairment (based on Child-Pugh classification) and matching healthy participants, pharmacokinetics of a single oral 100mg topiramate was determined. RESULTS: Compared with healthy controls, overall exposure (AUC0-∞) for topiramate was higher in mild-moderate (85%) and severe renal impairment (117%), consistent with significantly (p<0.05) lower apparent total body clearance (CL/F) and renal clearance (CLR), leading to longer elimination half-life. Both CLR and CL/F of topiramate correlated well with renal function. CL/F was comparable in ESRD and severe renal impairment. Half of usual starting and maintenance dose is recommended in moderate-severe renal impairment patients, and those with ESRD. Hemodialysis effectively removed plasma topiramate with mean dialysis clearance approximately 12-fold greater than CL/F (123.5 mL/min versus 10.8 mL/min). Compared with healthy matched, patients with moderate-severe hepatic impairment exhibited small increase (29%) in topiramate peak plasma concentrations and AUC0-∞ values, consistent with lower CL/F (26%). Topiramate was generally well tolerated. CONCLUSION: Half of usual dose is recommended for moderate-severe renal impairment and ESRD. Supplemental dose may be required during hemodialysis. Dose adjustments might not be required in moderate-severe hepatic impairments; however, the small sample size limits generalization.

Pharmacokinetic interactions between topiramate and diltiazem, hydrochlorothiazide, or propranolol.

Drug-drug interactions between topiramate and diltiazem, hydrochlorothiazide, or propranolol were evaluated along with safety/tolerability in three open-label studies. Healthy participants (aged 18-45 years) received topiramate 75 mg every 12 hours (q12h) and diltiazem 240 mg/day (study 1); topiramate 96 mg q12h and hydrochlorothiazide 25 mg/day (study 2); topiramate 100 mg q12h and propranolol 40-80 mg q12h (study 3). The pharmacokinetic parameters for topiramate, diltiazem (and active metabolites, desacetyldiltiazem [DEA], N-demethyl diltiazem [DEM]), hydrochlorothiazide, and propranolol (and its active metabolite) were assessed at steady state. Results showed no effect of diltiazem on topiramate pharmacokinetics. However, a modest reduction in systemic exposures of diltiazem and DEA (10-27%) occurred during coadministration with topiramate. Systemic exposure of DEM was unaffected. Furthermore, oral and renal clearance of topiramate decreased (22-30%) significantly (P < 0.05) during coadministration with hydrochlorothiazide, while systemic exposure increased by 27-29%. Topiramate had no effect on hydrochlorothiazide pharmacokinetics. The results demonstrated lack of pharmacokinetic interaction between topiramate and propranolol. Overall, no new safety concerns emerged when topiramate was coadministered with diltiazem, hydrochlorothiazide, or propranolol.

An open-label drug-drug interaction study of the steady-state pharmacokinetics of topiramate and glyburide in patients with type 2 diabetes mellitus.

BACKGROUND: Topiramate is approved for epilepsy and migraine headache management and has potential antidiabetic activity. Because topiramate and antidiabetic drugs may be co-administered, the potential drug-drug interactions between topiramate and glyburide (glibenclamide), a commonly used sulfonylurea antidiabetic agent, was evaluated at steady state in patients with type 2 diabetes mellitus (T2DM). METHODS: This was a single-center, open-label, phase I, drug interaction study of topiramate (150 mg/day) and glyburide (5 mg/day alone and concomitantly) in patients with T2DM. The study consisted of 14-day screening, 48-day open-label treatment, and a 7-day follow-up phase. Serial blood and urine were obtained and analyzed by liquid chromatography coupled mass spectrometry/mass spectrometry for topiramate, glyburide, and its active metabolites M1 (4-trans-hydroxy-glyburide) and M2 (3-cis-hydroxy-glyburide) concentrations. Pharmacokinetic parameters were estimated by model-independent methods. Changes in fasting plasma glucose from baseline and safety parameters were monitored throughout the study. RESULTS: Of 28 enrolled patients, 24 completed the study. Co-administration of topiramate resulted in a significant (p < 0.05) decrease in the glyburide area under the concentration-time curve (25 %) and maximum plasma concentration (22 %), and reduction in systemic exposure of M1 (13 %) and M2 (15 %). Renal clearance of M1 (13 %) and M2 (12 %) increased during treatment with topiramate. Steady-state pharmacokinetics of topiramate were unaffected by co-administration of glyburide. Co-administration of topiramate and glyburide was generally tolerable in patients with T2DM. CONCLUSION: Glyburide did not affect the pharmacokinetics of topiramate. Co-administration of topiramate decreased systemic exposure of glyburide and its active metabolites; combined treatment may require dosing adjustments of glyburide as per clinical judgment and glycemic control.

Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus.

This study characterized single- and multiple-dose pharmacokinetics of canagliflozin and its O-glucuronide metabolites (M5 and M7) and pharmacodynamics (renal threshold for glucose [RTG ], urinary glucose excretion [UGE0-24h ], and 24-hour mean plasma glucose [MPG0-24h ]) of canagliflozin in subjects with type 2 diabetes. Thirty-six randomized subjects received canagliflozin 50, 100, or 300 mg/day or placebo for 7 days. On Days 1 and 7, area under the plasma concentration-time curve and maximum observed plasma concentration (Cmax ) for canagliflozin and its metabolites increased dose-dependently. Half-life and time at which Cmax was observed were dose-independent. Systemic molar M5 exposure was half that of canagliflozin; M7 exposure was similar to canagliflozin. Steady-state plasma canagliflozin concentrations were reached by Day 4 in all active treatment groups. Pharmacodynamic effects were dose- and exposure-dependent. All canagliflozin doses decreased RTG , increased UGE0-24h , and reduced MPG0-24h versus placebo on Days 1 and 7. On Day 7, placebo-subtracted least-squares mean decreases in MPG0-24h ranged from 42-57 mg/dL with canagliflozin treatment. Adverse events (AEs) were balanced between treatments; no treatment-related serious AEs, AE-related discontinuations, or clinically meaningful adverse changes in routine safety evaluations occurred. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in subjects with type 2 diabetes supports a once-daily dosing regimen.