Cardiac Surgery-Related Acute Kidney Injury _ Risk Factors, Clinical Course, Management Suggestions.

OBJECTIVE: Acute kidney injury (AKI) is a common complication after cardiac surgery (CS). Because a therapeutic regimen remains scarce, the early implementation of preventive strategies is crucial. The authors investigated risk factors and the typical clinical course of CS-associated AKI (CS-AKI) to derive strategies for perioperative clinical routines. DESIGN: Retrospective data analysis. SETTING: The data were collected from clinical routines in a maximum care university hospital. PARTICIPANTS: Patients. INTERVENTIONS: The authors retrospectively analyzed data from 538 patients who underwent CS. MEASUREMENTS AND MAIN RESULTS: The median age of the 466 patients included was 66.6 years; 65.7% were men. AKI occurred in 131 (28.1%) patients, mainly (89.0%) starting postoperatively within 72 hours p. Thirty-one (6.7%) patients showed Kidney Disease Improving Global Outcome AKI stage 3. AKI was significantly more frequent in patients with chronic kidney disease (p < 0.001), emergency admission (p < 0.001), heart failure (p < 0.001), and postoperative complications (p < 0.001). In a multivariate analysis, postoperative CS-AKI risk significantly decreased with each 1 or 10 mL/min preoperative glomerular filtration rate (GFR) (odds ratio, 0.962 and 0.677; 95% confidence interval, 0.947-0.977 and 0.577-0.793; p < 0.001 and p < 0.0001). Only in patients who developed Kidney Disease Improving Global Outcome AKI stage 3, an early postoperative trend to decreased GFR and increased creatinine levels was observed. CONCLUSIONS: Especially in patients with preexisting CKD and signs of CS-AKI occurring on the day of surgery, close monitoring of renal function should be performed for at least 72 hours after CS to detect an onset of AKI early and initiate renal protective strategies. Optimal preoperative fluid management might prevent postoperative AKI.

Ularitide as treatment of refractory ascites in cirrhosis- a study protocol for a randomised trial.

INTRODUCTION Ascites is a frequent complication to cirrhosis. When ascites becomes refractory to standard diuretic pharmacotherapy, patients are facing a median survival of less than one year and most likely a need for frequent hospitalisations due to large-volume paracentesis or complications. An unmet need exists for new and improved treatments of refractory ascites and the present study investigates the potential of the natriuretic peptide ularitide for this indication. METHODS We aim to investigate the effects, safety and tolerability of ularitide as treatment of refractory ascites in cirrhosis patients in a randomised, double-blind, placebo-controlled trial. Participants receive ularitide or placebo as a continuous intravenous infusion during hospitalisation as an add-on to any diuretic treatment. Clinical end points include increase in diuresis and natriuresis, reduction in body weight and waist circumference, safety end points, as well as changes in plasma concentrations of renal and systemic response biomarkers and hormones. CONCLUSION This study will provide evidence concerning the potential of ularitide in treating cirrhosis patients with refractory ascites. FUNDING This investigator-initiated trial is supported by ADS AIPHIA Development Services AG. TRIAL REGISTRATION Clinicaltrials.gov (NCT04311489) and EU Drug Regulating Authorities Clinical Trials (EudraCT: 2019-002268-28). The trial will be conducted in accordance with good clinical practice, the Declaration of Helsinki and applicable demands from Danish authorities.

Preclinical characterisation of NSAIDs in ultradeformable carriers or conventional topical gels.

We compared in vivo transport and biodistribution of ketoprofen applied on the skin in ultradeformable carriers (Diractin) or a conventional topical gel (Gabrilen) with oral drug (Oruvail); for reference we used in vitro study data. The drug from Gabrilen diffuses into body with low bioavailability (<10%) and limited regio-selectivity (AUC(deep muscle/plasma) approximately 45/0.8 (t=0-8h), reaching maximum concentration in subcutaneous tissues and plasma at similar time (t(max) approximately 3-4h). The apparent drug elimination half-life is then similar to oral ketoprofen (t1/2,a) approximately 2 h). In contrast, Diractin containing ultradeformable carriers (Transfersome vesicles) delivers the drug more efficiently (>50%) and more directly into peripheral muscles (AUC(deep muscle/plasma) approximately 447/0.7 (652/1.4) for t=0-8 (0-24)h; tmax approximately 1 h), arguably in non-diffusive fashion. Ketoprofen from Diractin moreover disappears from body periphery slower (t1/2,a) approximately 4-6 h), owing to sustained drug release from the carriers in target tissue. Final clearance always proceeds via plasma (tmax approximately 4 h). Epicutaneous application of ketoprofen in conventional gels or the carrier-based formulation thus leads to different local accumulations and clearances. Ketoprofen from Diractin achieves more desirable biodistribution and clearance, arguably due to spontaneous carrier-mediated drug transport across the skin, which ensures local and relatively long-lasting drug deposition into peripheral target tissues.

Occlusion effect on transcutaneous NSAID delivery from conventional and carrier-based formulations.

We studied skin occlusion effects in vitro and in vivo on local and systemic delivery of ketoprofen across the organ, using the drug in a conventional non-occlusive topical gel (Togal Mobil-Gel), an occlusive tape (Mohrus), and the new targeted analgesic (Diractin), comprising ultradeformable, hydrophilic carriers in the form of a Transfersome vesicle. In vitro occluded skin permeability to ketoprofen from the tape (0.086cmh(-1)) marginally exceeds the value for the drug from carriers in a gel (0.058cmh(-1)), which resembles conventional gel on open excised skin (0.057cmh(-1)); smallness of occlusion-induced permeation enhancement ( approximately 1.5x) may be due to the high tested applied dose. In contrast, open skin permeability to the drug from the carriers in vitro is approximately 15xlower (0.004cmh(-1)). The benefit of ketoprofen association with the carriers for targeted transcutaneous delivery only shows-up in vivo after an non-occlusive epicutaneous application: the area under the curve (AUC) in peripheral deep muscle for the carrier-based gel then exceeds AUC for conventional gel approximately 35-fold. The AUC for occluded ultradeformable, hydrophilic carriers measured in living pigs is conversely approximately 10x lower, being 1.4-2.2x below that of the tape that is inferior to non-occluded carriers formulation (normalised cmax: approximately 200x). Occlusion thus disables ultradeformable, hydrophilic carriers by eliminating transcutaneous hydration gradient that normally drives the carriers across the skin. Compared with other non-steroidal anti-inflammatory agents (NSAIDs) for local usage, Diractin is thus evidently well differentiated and innovative.

A 12-week randomized study of topical therapy with three dosages of ketoprofen in Transfersome® gel (IDEA-033) compared with the ketoprofen-free vehicle (TDT 064), in patients with osteoarthritis of the knee.

OBJECTIVE: To evaluate the safety and efficacy of ketoprofen in Transfersome® gel (IDEA-033) in comparison with a ketoprofen-free vehicle (TDT 064) for the treatment of osteoarthritis (OA) of the knee. METHODS: Patients with knee OA (N = 866) were randomly assigned to receive topical IDEA-033 containing 100, 50, or 25 mg ketoprofen, or TDT 064 twice daily for 12 weeks, in a double-blind trial. The primary efficacy endpoint was the change in the Western Ontario and McMaster Universities (WOMAC®) Osteoarthritis Index pain subscale score. The coprimary efficacy endpoints were the WOMAC function subscale score and the patient global assessment of response to therapy. The secondary endpoints included the numeric pain rating for the first 14 days of treatment and the Outcome Measures in Rheumatology (OMERACT)-Osteoarthritis Research Society International (OARSI) responder rates. RESULTS: The WOMAC pain scores were reduced by approximately 50% or more in all four groups. The 100 and 50 mg ketoprofen groups, but not the 25 mg group, showed a superior reduction in the WOMAC pain score versus the TDT 064 group (100 mg: -57.4% [P = 0.0383]; 50 mg: -57.1% [P = 0.0204]; and 25 mg: -53.4% [P = 0.3616] versus TDT 064: -49.5%). The superiority of the ketoprofen-containing formulations was not demonstrated for the WOMAC function subscale score, whereas the patient global assessment of 50 mg ketoprofen group, but not the 100 or 25 mg group, was superior to that of the TDT 064 group (P = 0.0283). Responder rates were significantly higher for all the IDEA-033 groups versus the TDT 064 group, but were high in all groups (100 mg: 88.6%; 50 mg: 86.8%; 25 mg: 88.6%; and TDT 064: 77.5%). Dermal reactions were the only relevant drug-related adverse events in all four groups. CONCLUSION: The 50 and 100 mg ketoprofen doses of IDEA-033 were only marginally superior to TDT 064 for reducing pain associated with knee OA. The study indicates a high treatment response to the topical ketoprofen-free vehicle TDT 064.

Efficacy of epicutaneous Diractin (ketoprofen in Transfersome gel) for the treatment of pain related to eccentric muscle contractions.

OBJECTIVE: To investigate the effect of epicutaneously applied Diractin (ketoprofen in Transfersome gel) on pain induced by eccentric muscle contractions. METHODS: Three pilot studies which were subsequently pooled for a meta-analysis compared the efficacy of a single application of 25 mg ketoprofen in Diractin to 25 mg oral ketoprofen and placebo for the treatment of pain induced by 50 eccentric contractions of the elbow flexor muscles. In addition, the effect of multiple usage of up to 100 mg ketoprofen in Diractin bid over seven days on pain induced by walking down stairs with a total altitude of 200 meters was investigated. RESULTS: A single dose of 25 mg ketoprofen in Diractin after the elbow flexion exercise was significantly superior to placebo from 5 to 12 hours after treatment and also to oral ketoprofen at some time points after treatment. In contrast, oral ketoprofen was not different to placebo at any time after treatment. Multiple doses of up to 100 mg ketoprofen Diractin provided significant more pain relief than placebo on muscle pain induced by walking down stairs. CONCLUSIONS: Eccentric exercise-induced muscle soreness was shown to be an appropriate acute pain model to evaluate the efficacy of nonsteroidal anti-inflammatory drugs applied epicutaneously with Transfersome carriers. Diractin proved to be efficacious in relieving pain from eccentric muscle contractions and muscle over-exercise, respectively. The effect needs to be confirmed in a larger prospective clinical trial.

Efficacy and safety of epicutaneous ketoprofen in Transfersome (IDEA-033) versus oral celecoxib and placebo in osteoarthritis of the knee: multicentre randomised controlled trial.

OBJECTIVE: To compare epicutaneous ketoprofen in Transfersome (ultra-deformable vesicles, IDEA-033) versus oral celecoxib and placebo for relief of signs and symptoms in knee osteoarthritis. METHODS: This was a multicentre, randomised, double-blind, controlled trial; 397 patients with knee osteoarthritis participated and 324 completed the trial. They were randomly assigned 110 mg epicutaneous ketoprofen in 4.8 g Transfersome plus oral placebo (n = 138), 100 mg oral celecoxib plus placebo gel (n = 132), or both placebo formulations (n = 127) twice daily for 6 weeks. Primary efficacy outcome measures were the changes from baseline to end of the study on the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain subscale, physical function subscale and patient global assessment (PGA) of response. RESULTS: The mean WOMAC pain subscale scores in the intent to treat population were reduced by 18.2 (95% confidence interval -22.1 to -14.3), 20.3 (-24.3 to -16.2) and 9.9 (-13.9 to -5.8) in the IDEA-033, celecoxib and placebo groups, respectively, and the physical function subscale score by 14.6 (-18.1 to -11.0), 16.6 (-20.2 to -13.0) and 10.2 (-13.8 to -6.6), respectively. The mean PGA of response scores were 1.8 (1.6 to 2.1), 1.7 (1.5 to 1.9) and 1.3 (1.1 to 1.5), respectively. The differences in change between IDEA-033 and placebo were statistically significant for pain subscale (p<0.01) and PGA of response (p<0.01). Gastrointestinal adverse events for IDEA-033 were similar to placebo. CONCLUSION: IDEA-033 is superior to placebo and comparable with celecoxib in relieving pain associated with an acute flare of knee osteoarthritis.