Vascular effects of serelaxin in patients with stable coronary artery disease: a randomized placebo-controlled trial.

AIMS: The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD). METHODS AND RESULTS: In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of -9.6 mmHg (P = 0.01) and -13.5 mmHg (P = 0.0003) for systolic blood pressure and -5.2 mmHg (P = 0.02) and -8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (-0.24 vs. -0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up. CONCLUSION: In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

Subcutaneous injection of diclofenac for the treatment of pain following minor orthopedic surgery (DIRECT study): a randomized trial.

OBJECTIVES: Parenteral diclofenac is frequently used for analgesia following minor orthopedic interventions. Currently available diclofenac formulations are for intramuscular (IM) or intravenous injection. A new 1 mL volume formulation of diclofenac containing hydroxypropyl-ß-cyclodextrin (HPßCD) allows both SC and IM administration. The objective of this open-label, randomized, parallel group, active-controlled study was to assess the safety and efficacy of 75 mg diclofenac HPßCD, administered SC or IM, compared with IM Voltaren® 75 mg in inpatients undergoing minor orthopedic surgeries with moderate-to-severe postoperative pain. METHODS: A total of 325 patients were randomized to treatment. Surgery-related pain was comparable between groups before treatment and rapidly declined in all patients following diclofenac injection. The primary endpoint was investigator-assessed local tolerability up to 18 hours postinjection (redness, swelling, and hardening at the injection site each scored on a 4-point scale where 0 = none, 1 = mild, 2 = moderate, and 3 = severe). RESULTS: Local tolerability was found to be optimal for all the injected formulations, with mean overall scores (0 to 9) of 0.57, 0.31, and 0.26, for diclofenac HPßCD SC, diclofenac HPßCD IM, and Voltaren® IM, respectively. Consistently, the overall tolerability as judged by the patients and investigators was reported as good or excellent in more than 90% of cases in all groups. CONCLUSIONS: Overall, the study results indicate that safety and efficacy were similar irrespective of the diclofenac formulation used; thus, the new SC diclofenac HPßCD has an acceptable tolerability profile and may be considered a valid alternative to IM-delivered diclofenac formulations.

Efficacy and safety of low dose subcutaneous diclofenac in the management of acute pain: a randomized double-blind trial.

OBJECTIVE: Diclofenac is an effective and well-tolerated nonsteroidal anti-inflammatory drug (NSAID) frequently used in the treatment of acute pain. Marketed formulations for parenteral administration usually contain 75 mg/3 mL of diclofenac sodium, which provide limited dosing flexibility, and are usually given intramuscularly. METHODS: We present a randomized, double-blind, active comparator- and placebo-controlled, parallel-group phase III multicenter study, investigating efficacy and tolerability of a new 1 mL-volume formulation of diclofenac sodium (25, 50 or 75 mg) containing hydroxypropyl-ß-cyclodextrin (HPßCD) as a solubility enhancer. This low-volume formulation allows subcutaneous (SC), in addition to intramuscular (IM) administration. Patients developing moderate-to-severe pain (≥ 50 mm on Visual Analogue Scale) after third molar extraction under local anesthesia were randomized to one of the 4 SC injections: 25 mg diclofenac HPßCD (n = 77), 50 mg diclofenac HPßCD (n = 76), 75 mg diclofenac HPßCD (n = 78), or placebo (n = 75). RESULTS: Mean pain intensity difference at 1.5 hours postdose (primary endpoint) was higher in all diclofenac-treated groups than placebo group. The adjusted means (95% CI) were 36.5 (31.7 to 41.2) in diclofenac 25 mg group, 37.3 (32.6 to 42.1) in diclofenac 50 mg group, 37.7 (33.0 to 42.4) in diclofenac 75 mg group, and 12.3 (7.44 to 17.1) in placebo group. Both 25 and 50 mg doses of diclofenac produced significantly greater pain relief than placebo (P < 0.001 in both comparisons). CONCLUSION: Single SC doses of diclofenac HPßCD of 25 and 50 mg are effective and well tolerated for relieving pain compared with placebo.

Pharmacokinetics of a new subcutaneous diclofenac formulation administered to three body sites: quadriceps, gluteus, and abdomen.

OBJECTIVE: To assess the relative bioavailability of a new subcutaneous (SC) diclofenac hydroxypropyl b-cyclodextrin (HPbCD) formulation administered to three body sites: quadriceps, gluteus, and abdomen. MATERIALS AND METHODS: This was a pilot, single-dose, randomized, three-way crossover relative bioavailability study. A total of 12 healthy subjects received a single SC injection of diclofenac HPbCD 50 mg/1 mL in the quadriceps, gluteus, or abdomen. RESULTS: The AUC was comparable after SC diclofenac HPbCD in the quadriceps, gluteus, and abdomen. The Cmax was comparable after SC administration in the quadriceps or abdomen, and ~ 17% higher in the gluteus. The absorption was rapid (30 minutes) after administration of the treatment at any site. The treatment was well tolerated. CONCLUSIONS: The relative bioavailability of SC diclofenac HPbCD was comparable when administered to the quadriceps, gluteus, and abdomen. The new diclofenac formulation can therefore be administered subcutaneously to any of these sites without clinically significant differences. A further adequately powered study would be necessary to reveal any differences among injection sites in terms of peak plasma concentration.

Efficacy and tolerability of DHEP-heparin plaster in reducing pain in mild-to-moderate muscle contusions: a double-blind, randomized trial.

OBJECTIVES: To investigate if the 180-mg diclofenac epolamine and heparin sodium 5600 IU medicated plaster (DHEP-heparin) is more effective for pain reduction in mild-to-moderate contusions than the reference diclofenac epolamine 180 mg plaster (DHEP). RESEARCH DESIGN AND METHODS: This multicenter, multinational, prospective, double-blind versus reference comparator and versus placebo, controlled trial had balanced random assignment in three parallel treatment groups. The DHEP-heparin medicated plaster was compared to the DHEP medicated plaster and a placebo medicated plaster. A total of 331 outpatients, aged ≥18 and ≤65 years, with unilateral mild-to-moderate muscle contusion, pain on standardized movement of ≥50 mm, and superficial hematoma of ≤10 × 14 cm(2) completed the study. Plasters were applied each morning, for ≥20 hours daily for 14 consecutive days. Outcomes were assessed in three visits, over 14 days, plus patients' daily self-assessment. CLINICAL TRIAL REGISTRATION: 05DCz/FHp11 - Eudra CT n: 2005-003829-31 MAIN OUTCOME MEASURES: Primary efficacy endpoint was mean change from baseline in pain on movement after 3 days of treatment, compared between groups. Secondary efficacy endpoints included mean daily change from baseline in pain on movement during treatment, pain level as assessed at control visits after 7 and 14 days, time (days) to hematoma disappearance based on patients' daily evaluations, rescue medication use, and overall treatment efficacy as judged by both patients and investigators. RESULTS: Pain progressively declined in all groups, more rapidly in DHEP-heparin recipients, compared to DHEP, and in both active treatment groups compared to placebo. Adverse events were recorded in 24 of the 355 (6.7%) exposed patients, and generally resolved without need to interrupt treatment. CONCLUSION: The DHEP-heparin plaster is superior to the reference DHEP plaster in reducing pain associated with mild-to-moderate muscle contusion. Both active treatments were significantly more effective than placebo, and each showed a comparably favorable, placebo-like safety profile.

Pharmacokinetics of a new diclofenac sodium formulation developed for subcutaneous and intramuscular administration.

OBJECTIVE: To assess the relative bioavailability of diclofenac sodium hydroxypropyl ß-cyclodextrin (HPßCD) administered via the subcutaneous (s.c.) and intramuscular (i.m.) route versus Voltaren® i.m. and to evaluate the dose linearity and pharmacokinetics of the s.c. formulation at three dose levels. Safety and local tolerability were also assessed. MATERIALS AND METHODS: One single-dose, randomized, three-way, crossover relative bioavailability study and one linearity single escalating dose, randomized, three-way cross-over pharmacokinetic study were conducted at two different clinical sites. A total of 42 healthy male and female subjects participated in both studies. Subjects received 75 mg/ml diclofenac sodium HPßCD (i.m. and s.c.) and Voltaren® 75 mg/3 ml (i.m.) in Study 1 and 25, 50, or 75 mg/ml diclofenac sodium HPßCD (s.c.) in Study 2. RESULTS: Study 1 demonstrated bioequivalence of the s.c. test formulation with Voltaren® i.m. with respect to Cmax and AUC. Bioequivalence of the test i.m. with Voltaren® i.m. was also demonstrated (except the upper limit of the 90% confidence interval (CI) for Cmax which marginally exceeded the 80 - 125% range (125.78%)). Study 2 demonstrated that after s.c. administration of the test formulation, both Cmax and AUC are linearly related to the tested diclofenac doses. All tested doses were safe and locally well-tolerated with no serious adverse events reported. CONCLUSION: Bioequivalence of diclofenac HPßCD 75 mg/ml after s.c. and i.m. administration with Voltaren® i.m. was demonstrated, except for the marginal deviation in Cmax when comparing the i.m. test and Voltaren®. Linearity was also demonstrated for the three doses intended for marketing.