Adjunctive therapy with the Tie2 agonist Vasculotide reduces pulmonary permeability in Streptococcus pneumoniae infected and mechanically ventilated mice.

Community acquired pneumonia, mainly caused by Streptococcus pneumoniae (S.pn.), is a common cause of death worldwide. Despite adequate antibiotic therapy, pneumococcal pneumonia can induce pulmonary endothelial hyperpermeability leading to acute lung injury, which often requires mechanical ventilation (MV) causing ventilator-induced lung injury (VILI). Endothelial stabilization is mediated by angiopoietin-1 induced Tie2 activation. PEGylated (polyethylene glycol) Tie2-agonist Vasculotide (VT) mimics Angiopietin-1 effects. Recently, VT has been shown to reduce pulmonary hyperpermeability in murine pneumococcal pneumonia. The aim of this study was to determine whether VT reduces lung damage in S.pn. infected and mechanically ventilated mice. Pulmonary hyperpermeability, immune response and bacterial load were quantified in S.pn. infected mice treated with Ampicillin + /-VT and undergoing six hours of MV 24 h post infection. Histopathological lung changes, Tie2-expression and -phosphorylation were evaluated. VT did not alter immune response or bacterial burden, but interestingly combination treatment with ampicillin significantly reduced pulmonary hyperpermeability, histological lung damage and edema formation. Tie2-mRNA expression was reduced by S.pn. infection and/or MV but not restored by VT. Moreover, Tie2 phosphorylation was not affected by VT. These findings indicate that VT may be a promising adjunctive treatment option for prevention of VILI in severe pneumococcal pneumonia.

Pharmacokinetics of Diclofenac and Hydroxypropyl-ß-Cyclodextrin (HPßCD) Following Administration of Injectable HPßCD-Diclofenac in Subjects With Mild to Moderate Renal Insufficiency or Mild Hepatic Impairment.

Given their established analgesic properties, nonsteroidal anti-inflammatory drugs (NSAIDs) represent an important postoperative pain management option. This study investigated: (1) the effects of mild or moderate renal insufficiency and mild hepatic impairment on the pharmacokinetics (PK) of diclofenac and hydroxypropyl-ß-cyclodextrin (HPßCD) following administration of the injectable NSAID HPßCD-diclofenac; and (2) the PK of HPßCD following administration of HPßCD-diclofenac and intravenous itraconazole formulated with HPßCD in healthy adults. Diclofenac clearance (CL) and volume of distribution (Vz ) tended to increase with decreasing renal function (moderate insufficiency versus mild insufficiency or healthy controls). Regression analysis demonstrated a significant relationship between Vz (but not CL or elimination half-life, t½ ) and renal function. HPßCD CL was significantly decreased in subjects with renal insufficiency, with a corresponding increase in t½ . There were no significant differences in diclofenac or HPßCD PK in subjects with mild hepatic impairment versus healthy subjects. Exposure to HPßCD in healthy subjects following HPßCD-diclofenac administration was ∼12% of that with intravenous itraconazole, after adjusting for dosing schedule and predicted accumulation (<5% without adjustment). With respect to PK properties, these results suggest that HPßCD-diclofenac might be administered to patients with mild or moderate renal insufficiency or mild hepatic impairment without dose adjustment (NCT00805090).

A metastasis biomarker (MetaSite Breast™ Score) is associated with distant recurrence in hormone receptor-positive, HER2-negative early-stage breast cancer.

Metastasis is the primary cause of death in early-stage breast cancer. We evaluated the association between a metastasis biomarker, which we call "Tumor Microenviroment of Metastasis" (TMEM), and risk of recurrence. TMEM are microanatomic structures where invasive tumor cells are in direct contact with endothelial cells and macrophages, and which serve as intravasation sites for tumor cells into the circulation. We evaluated primary tumors from 600 patients with Stage I-III breast cancer treated with adjuvant chemotherapy in trial E2197 (NCT00003519), plus endocrine therapy for hormone receptor (HR)+ disease. TMEM were identified and enumerated using an analytically validated, fully automated digital pathology/image analysis method (MetaSite Breast™), hereafter referred to as MetaSite Score (MS). The objectives were to determine the association between MS and distant relapse free interval (DRFI) and relapse free interval (RFI). MS was not associated with tumor size or nodal status, and correlated poorly with Oncotype DX Recurrence Score (r = 0.29) in 297 patients with HR+/HER2- disease. Proportional hazards models revealed a significant positive association between continuous MS and DRFI (p = 0.001) and RFI (p = 0.00006) in HR+/HER2- disease in years 0-5, and by MS tertiles for DRFI (p = 0.04) and RFI (p = 0.01), but not after year 5 or in triple negative or HER2+ disease. Multivariate models in HR+/HER- disease including continuous MS, clinical covariates, and categorical Recurrence Score (<18, 18-30, > 30) showed MS is an independent predictor for 5-year RFI (p = 0.05). MetaSite Score provides prognostic information for early recurrence complementary to clinicopathologic features and Recurrence Score.

Postoperative opioid sparing with injectable hydroxypropyl-ß-cyclodextrin-diclofenac: pooled analysis of data from two Phase III clinical trials.

PURPOSE: Use of nonopioid analgesics (including nonsteroidal anti-inflammatory drugs) for postoperative pain management can reduce opioid consumption and potentially prevent opioid-related adverse events. This study examined the postoperative opioid-sparing effect of repeated-dose injectable diclofenac formulated with hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac. PATIENTS AND METHODS: Pooled data from two double-blind, randomized, placebo- and active comparator-controlled Phase III trials were analyzed. Patients received HPßCD-diclofenac, placebo, or ketorolac by intravenous injection every 6 hours for up to 5 days following abdominal/pelvic or orthopedic surgery. Rescue opioid use was evaluated from the time of first study drug administration to up to 120 hours following the first dose in the overall study population and in subgroups defined by baseline pain severity, age, and HPßCD-diclofenac dose. RESULTS: Overall, 608 patients received ≥1 dose of study medication and were included in the analysis. While 93.2% of patients receiving placebo required opioids, the proportion of patients requiring opioids was significantly lower for patients receiving HPßCD-diclofenac (18.75, 37.5, or 50 mg) or ketorolac (P<0.005 for all comparisons). Mean cumulative opioid dose and number of doses were significantly lower among patients receiving HPßCD-diclofenac versus placebo for the 0-24 through 0-120 hour time periods (P<0.0001), as well as versus ketorolac for the 0-72 through 0-120 hour time periods (P<0.05). HPßCD-diclofenac significantly reduced opioid consumption versus placebo in subgroups based on baseline pain severity (moderate, severe) and age (<65 years, ≥65 years) from the 0-24 hour period onward. When compared to ketorolac, HPßCD-diclofenac also significantly reduced cumulative opioid consumption among patients with moderate baseline pain (0-72 through 0-120 hours) and opioid dose number among patients ≥65 years old (0-24 through 0-120 hours). CONCLUSION: HPßCD-diclofenac can reduce postoperative opioid requirements. As this analysis was not powered to compare opioid-related adverse event rates, follow-up studies examining the clinical impact of HPßCD-diclofenac's opioid sparing are warranted.

A Phase I study evaluating the effect of age and weight on the pharmacokinetics of an injectable formulation of diclofenac solubilized with hydroxypropyl-ß-cyclodextrin.

PURPOSE: The analgesic and opioid-sparing effects of nonsteroidal anti-inflammatory drugs can be beneficial in postoperative populations. Hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac is an injectable formulation of diclofenac solubilized with HPßCD that is administered as a low-volume intravenous bolus. This open-label, single-dose study examined the effects of age and weight on the pharmacokinetic (PK) profile of HPßCD-diclofenac. METHODS: Eighty-eight adult volunteers were enrolled. An age-based cohort included 34 subjects 55-82 years old stratified into three groups and receiving HPßCD-diclofenac 18.75 mg. A weight-based cohort included 54 subjects stratified into five groups based on body weight and body mass index and receiving HPßCD-diclofenac 37.5 mg. PK analysis was performed on blood samples collected predosing and at predefined intervals (5, 10, 20, 30, and 45 minutes; 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 18 hours) postdosing. Diclofenac PK parameters were examined in the individual cohorts, and regression analyses of the relationship between age, weight, and PK parameters were performed on pooled data from all enrolled subjects. RESULTS: Examination of the age-based cohort revealed similar diclofenac PK parameters across age groups. PK parameters were likewise similar across weight groups in the weight-based cohort. Regression analysis on pooled data from the age- and weight-based cohorts revealed that increasing body weight was associated with a significant increase in diclofenac clearance (CL), suggesting decreased exposure in high-weight patients. Analysis of the pooled population also demonstrated an inverse relationship between age and elimination half-life (t1/2), likely due to a decrease in the volume of distribution (Vz) with increased age, not a change in CL. There were no deaths, serious adverse events, or adverse events that led to discontinuation. CONCLUSION: This study suggests that the CL of diclofenac is not dependent on age in elderly subjects receiving HPßCD-diclofenac but indicates that diclofenac CL increases with increasing body weight.

A Pooled Analysis Evaluating Renal Safety in Placebo- and Active Comparator-Controlled Phase III Trials of Multiple-Dose Injectable HPßCD-Diclofenac in Subjects with Acute Postoperative Pain.

OBJECTIVE : While injectable nonsteroidal anti-inflammatory drugs (NSAIDs) are a key component of postoperative multimodal analgesia, renal safety concerns may limit use in some patients. This study examined the renal safety of injectable HPßCD-diclofenac when given for ≤ 5 days following orthopedic or abdominal/pelvic surgery. METHODS : Pooled analysis of data from two randomized, placebo- and active comparator-controlled phase III trials in 608 total patients was conducted. Renal safety was assessed by examining treatment-emergent adverse events (AEs) and postoperative blood urea nitrogen (BUN) and serum creatinine shifts. RESULTS : There were three renal AEs each in the HPßCD-diclofenac (n = 318 patients) and placebo (n = 148 patients) groups, and two renal AEs in the ketorolac group (n = 142 patients). No significant difference in renal AE risk was detected for patients receiving HPßCD-diclofenac (RR: 1.40 [0.15,13.3]; P = 0.75) or ketorolac (RR: 2.08 [0.19,22.7]; P = 0.56) versus placebo. All renal AEs were mild or moderate in severity, and a single renal AE (acute renal failure in a patient receiving HPßCD-diclofenac) was treatment-related. One incidence of postoperative shift to high (> upper limit of normal) serum creatinine occurred in the HPßCD-diclofenac group (n = 2 in the ketorolac group). Mean changes in serum creatinine or BUN did not differ significantly between patients receiving HPßCD-diclofenac and placebo. CONCLUSIONS : While this analysis examined relatively brief exposure typical for parenterally administered analgesics in the postoperative setting in patients with largely normal renal function, the results suggest that HPßCD-diclofenac use for acute postoperative pain may not be associated with added renal safety risks over placebo in this patient population.

Single-dose and multiple-dose pharmacokinetics and dose proportionality of intravenous and intramuscular HPßCD-diclofenac (Dyloject) compared with other diclofenac formulations.

STUDY OBJECTIVE: To evaluate single- and repeated-dose pharmacokinetics (PK) and dose proportionality of hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac compared with Voltarol after intravenous (IV) and intramuscular (IM) administration. DESIGN: Study 1: Single-dose randomized four-way crossover study. Study 2: Multiple-dose randomized three-way crossover study. SETTING: Clinical research center. SUBJECTS: Healthy adult volunteers. INTERVENTION: Study 1: Subjects received HPßCD-diclofenac and Voltarol, IV and IM, with a 5-day washout between treatment periods. Study 2: Subjects received two doses of IV HPßCD-diclofenac and oral Cataflam once every 6 hours for four doses with a 48-hour washout period between treatment periods. MEASUREMENTS AND MAIN RESULTS: Study 1: IV HPßCD-diclofenac had a higher peak plasma concentration (Cmax ) and earlier time to reach maximum plasma concentration (Tmax ), but equivalent plasma exposure (area under the curve from time zero to t [AUC0-t ]) to IV Voltarol. The geometric mean ratio of HPßCD-diclofenac (IV) to Voltarol (IV) for AUC0-t was 106.27%. The geometric mean ratio of HPßCD-diclofenac (IM) to Voltarol (IM) for AUC0-t was 110.91%. The geometric mean ratio of HPßCD-diclofenac (IV) to HPßCD-diclofenac (IM) for AUC0-t was 101.25%. The geometric mean ratio of HPßCD-diclofenac (IM) to Voltarol (IV) for AUC0-t was 104.96%. Study 2: Cmax for diclofenac was 2904 and 6031 ng/ml after the first IV dose of 18.75 and 37.5 mg HPßCD-diclofenac, respectively, and was 3090 and 5617 ng/ml after the fourth dose, indicating no accumulation. Plasma exposures to 18.75 mg (866 ng·hour/ml) and 37.5 mg (1843 ng·hour/ml) IV HPßCD-diclofenac bracketed that of oral Cataflam 50 mg (1473 ng·hour/ml). CONCLUSIONS: Study 1: Bioavailability in terms of AUC after IV administration was equivalent for HPßCD-diclofenac compared with Voltarol and after IM administration of HPßCD-diclofenac and Voltarol. Bioavailability in terms of AUC after IM administration of HPßCD-diclofenac was equivalent to IV administration of HPßCD-diclofenac and IV administration of Voltarol. Study 2: HPßCD-diclofenac showed dose proportionality after single- and multiple-dose administration and no accumulation of HPßCD-diclofenac. HPßCD-diclofenac was safe and well tolerated following IV and IM administration.

Effects of injectable HPßCD-diclofenac on the human delayed rectifier potassium channel current in vitro and on proarrhythmic QTc in vivo.

BACKGROUND: Novel formulations and administration routes of established drugs may result in higher maximum concentrations or total exposures and potentially cause previously unrecognized adverse events. OBJECTIVE: This study evaluated the proarrhythmic potential of hydroxypropyl-ß-cyclodextrin (HPßCD)-diclofenac, a novel injectable diclofenac formulation solubilized with hydroxypropyl-ß-cyclodextrin (HPßCD), on ventricular electrical conduction in preclinical and clinical models. METHODS: We assessed the effects of diclofenac, HPßCD, and HPßCD-diclofenac on the human delayed rectifier potassium channel (IKr) using human embryonic kidney (HEK) 293 cells transfected with a human ether-à-go-go-related gene (hERG) using whole-cell patch-clamp. In a single-dose, active- and placebo-controlled, 4-period crossover, thorough QT in vivo study, 70 healthy volunteers (mean age, 23.3 years; range, 18-49 years; 55.75% male) received HPßCD-diclofenac at 37.5- and 75-mg doses, inactive vehicle (placebo), and an active control (moxifloxacin). RESULTS: In vitro, diclofenac produced no statistically significant effect on IKr. Significant, non-dose-dependent effects were observed in the presence of HPßCD or HPßCD-diclofenac of similar magnitude across the 300-fold dose range of concentrations tested, suggesting an artifact due to the detergent effect of HPßCD in this in vitro model. In vivo, neither HPßCD-diclofenac dose resulted in QTc prolongation ≥2 ms (≥5 ms is the threshold of clinical concern). No correlation was evident between changes in QTc and plasma concentrations of diclofenac or HPßCD. Confirming study sensitivity, moxifloxacin produced a mean QTc prolongation >10 ms. CONCLUSIONS: The findings from the present study suggest that HPßCD-diclofenac does not have a dose-dependent effect in the in vitro hERG assay system and does not produce proarrhythmic QTc prolongation in vivo. ClinicalTrials.gov identifier: NCT01812538.

Analgesic efficacy and safety of a novel injectable formulation of diclofenac compared with intravenous ketorolac and placebo after orthopedic surgery: a multicenter, randomized, double-blinded, multiple-dose trial.

OBJECTIVES: A novel injectable formulation of diclofenac, Dyloject, utilizes hydroxypropyl-ß-cyclodextrin (HPßCD) as a solubilizing agent, allowing dosing as a small-volume intravenous bolus for postoperative pain. In this test of the efficacy and safety of HPßCD diclofenac, we hypothesized that HPßCD diclofenac would relieve moderate and severe pain after orthopedic surgery. PATIENTS AND METHODS: Adults 18 to 85 years old with moderate and severe pain within 6 hours after surgery were randomized to HPßCD diclofenac, ketorolac tromethamine, or placebo, and stratified by risk cohort. The HPßCD diclofenac non-high-risk cohort dose was 37.5 mg, the high-risk cohort received 18.75 mg, and patients ≥95 kg received 50 mg. The ketorolac dose was 30 mg in the non-high-risk and high-weight cohorts and 15 mg in the high-risk cohort. Rescue intravenous morphine was given for pain as needed. Efficacy was measured by the sum of pain intensity differences (SPID). RESULTS: Mean SPID scores of 277 patients were significantly better with HPßCD diclofenac and ketorolac than with placebo (P<0.0001), across all risk cohorts (P<0.05). HPßCD diclofenac was associated with better SPID scores, faster onset of analgesia, and significantly lower opioid requirement (P<0.008) than ketorolac. In patients more than or equal to 65 years, HPßCD diclofenac was associated with significantly better analgesic efficacy (P=0.05), and lower opioid requirement versus ketorolac. The incidence of treatment-related adverse events was similar across groups. DISCUSSION: HPßCD diclofenac is safe and efficacious for acute moderate and severe pain after orthopedic surgery and significantly spares morphine use.

A novel injectable formulation of diclofenac compared with intravenous ketorolac or placebo for acute moderate-to-severe pain after abdominal or pelvic surgery: a multicenter, double-blind, randomized, multiple-dose study.

BACKGROUND: Injectable formulations of diclofenac have long been available in Europe and other countries. These formulations use a default dose of 75 mg of diclofenac delivered IV over 30 to 120 minutes or as an IM injection. A novel formulation of injectable diclofenac sodium, Dyloject®, is solubilized with hydroxypropyl ß-cyclodextrin (HPßCD) so that it can be given IV or IM in a small volume bolus. In this multicenter, multiple-dose, multiple-day, randomized, double-blind, parallel-group phase 3 study, we investigated whether lower doses of HPßCD diclofenac delivered as a small volume bolus would be effective for the management of acute pain after abdominal or pelvic surgery. METHODS: Adults with moderate and severe pain, defined as ≥50 mm on a 0 to 100 mm visual analog scale, within 6 hours after surgery were randomly assigned (1:1:1:1 ratio) to receive HPßCD diclofenac, 18.75 mg or 37.5 mg; ketorolac tromethamine 30 mg; or placebo. Patients in all treatment arms received a bolus IV injection every 6 hours until discharged. They were observed for at least 48 h, and for up to 5 days. Rescue IV morphine was available any time, up to a total of 7.5 mg over a 3-hour period. The primary efficacy measure was the sum of pain intensity differences from 0 to 48 hours after study drug initiation. RESULTS: Three hundred thirty-one patients received ≥1 dose of study drug. Over the first 48 hours, both IV HPßCD diclofenac doses, as well as ketorolac, produced significant reductions in pain intensity over placebo (all P < 0.05), as well as significant reductions in the need for rescue morphine administration. Both doses of HPßCD diclofenac, as well as ketorolac, significantly reduced rescue morphine dosages, as compared to placebo (P < 0.0001), and time to rescue morphine administration was significantly increased by treatment with 18.75 mg diclofenac and ketorolac. The overall incidence of treatment-related adverse events was 20.2%. No treatment-related serious adverse events were reported in either diclofenac dose group, whereas only 1 was reported in the ketorolac group. CONCLUSIONS: For patients with acute moderate and severe pain after abdominal or pelvic surgery, repeated 18.75 mg and 37.5 mg doses of HPßCD diclofenac provided significant analgesic efficacy, as compared to placebo. Significant analgesic efficacy was also provided by the active comparator ketorolac. Both HPßCD diclofenac and ketorolac significantly reduced the need for opioids.

A double-blind placebo-controlled comparison of a novel formulation of intravenous diclofenac and ketorolac for postoperative third molar extraction pain.

Dyloject is a novel formulation of diclofenac intended for intravenous (IV) administration. This formulation employs the solubilizing agent hydroxypropyl-ß-cyclodextrin to permit bolus IV administration. The efficacy and safety of 5 dose levels of IV diclofenac were compared with IV ketorolac and placebo following third molar extraction. This was a single-dose, randomized, double-blind, placebo- and comparator-controlled, parallel-group study. A total of 353 subjects with moderate to severe pain received placebo; ketorolac 30 mg; or IV diclofenac 3.75, 9.4, 18.75, 37.5, or 75 mg (N  =  51 for all groups, except N  =  47 for ketorolac). The primary endpoint was total pain relief over 6 hours (TOTPAR6) as measured by the visual analog scale (VAS). Secondary endpoints included multiple measures of pain intensity and relief; patient global evaluation; and times to pain relief and rescue medication. Dropouts and adverse effects (AEs) were also monitored. IV diclofenac was superior to placebo as measured by TOTPAR6 (P < .0001 for all doses except 3.75 mg, for which P  =  .0341). IV diclofenac 3.75 mg was statistically superior to placebo for TOTPAR2 and TOTPAR4. IV diclofenac at both 37.5 and 75 mg was superior to placebo (P < .05) at the earliest (5 minute) assessments of pain intensity and pain relief, but ketorolac was not. The proportion of patients reporting 30% or greater pain relief at 5 minutes was significantly greater after IV diclofenac 37.5 and 75 mg than after ketorolac 30 mg or placebo. Secondary endpoints confirmed the primary findings. Treatment-related AEs were generally mild to moderate and were typical for nonsteroidal anti-inflammatory drugs (NSAIDs). The more rapid onset of action of IV diclofenac compared with the reference injectable NSAID ketorolac suggests additional clinical benefit. If confirmed in larger series, these findings may improve the safety and efficacy of postoperative NSAID analgesia.

The analgesic efficacy and safety of a novel intranasal morphine formulation (morphine plus chitosan), immediate release oral morphine, intravenous morphine, and placebo in a postsurgical dental pain model.

BACKGROUND: Opioids are standard treatment for postoperative pain. In this study, we compared the safety and efficacy of intranasal (i.n.) morphine to i.v. and oral morphine and placebo. METHODS: Two-hundred-twenty-five patients with moderate-to-severe pain after third molar extraction were randomized to receive a single dose of i.n. morphine 7.5 mg or 15 mg, i.v. morphine 7.5 mg, oral morphine 60 mg or placebo. Pain intensity was assessed using visual analog and categorical scales, and pain relief using a categorical scale. Outcomes included total pain relief, pain intensity difference, summed pain intensity difference, time to analgesic onset, time to requesting rescue medication, and patients' global evaluation of their treatment. Safety assessments included adverse event recording and nasal examinations. RESULTS: Across the various efficacy outcomes, both i.n. morphine doses were statistically similar to the positive comparators (i.v. and oral morphine), and all four morphine treatments were statistically superior to placebo. Overall, i.n. morphine 15 mg presented an efficacy profile similar to i.v. morphine 7.5 mg; both treatments demonstrated rapid onset of efficacy, generally persistent throughout the 6-h assessment period. The lower dose of i.n. morphine, 7.5 mg, was statistically similar to the other active treatments at 2 h and 6 h and similar to placebo at 4 h. Study medications were generally well tolerated, with no withdrawals due to adverse events or other safety concerns, and no serious adverse events reported. The most frequently reported adverse events were typical systemic opioid effects. CONCLUSIONS: I.n. morphine offers a noninvasive alternative to i.v. morphine for postoperative analgesia.

Dyloject, a novel injectable diclofenac formulation, offers greater safety and efficacy than voltarol for postoperative dental pain.

BACKGROUND AND OBJECTIVES: Voltarol for injection (a diclofenac sodium formulation employing polyethylene glycol and benzyl alcohol [PG-BA] as excipients) is marketed in Europe but not in North America. A suspension, PG-BA diclofenac sodium, requires preparation for each patient and slow IV infusion to minimize venous irritation. Dyloject, a novel diclofenac formulation, employs hydroxypropyl beta-cyclodextrin (HPbetaCD) to solubilize diclofenac in a small volume. We compared the efficacy and safety of an IV HPbetaCD diclofenac sodium bolus, a 30-minute PG-BA diclofenac sodium infusion, and placebo in post-molar extraction pain. METHODS: A total of 155 adult patients were randomized to receive HPbetaCD diclofenac sodium 75 mg, PG-BA diclofenac sodium 75 mg, or placebo. Primary endpoints were superiority of HPbetaCD diclofenac sodium to placebo and noninferiority of HPbetaCD diclofenac sodium to PG-BA diclofenac sodium with respect to total pain relief over 4 hours (TOTPAR4) on a 0 to 100-mm visual analog scale (VAS). Secondary endpoints included categorical TOTPAR4, VAS and categorical TOTPAR up to 8 hours, other measures of pain intensity and relief, patient global evaluation, and time to rescue medication. RESULTS: HPbetaCD diclofenac sodium had efficacy superior to both placebo and PG-BA diclofenac sodium. At 15 minutes, more patients given HPbetaCD diclofenac sodium than PG-BA diclofenac sodium reported 30% reduction in pain intensity (52% vs. 21%, P = .0022). Both diclofenac products had a 6-hour duration of effect and were well tolerated. Patient global evaluations of HPbetaCD diclofenac sodium were high, superior to placebo, and similar to PG-BA diclofenac sodium. The adverse event (AE) incidence was similar for HPbetaCD diclofenac sodium and PG-BA diclofenac sodium, except that in the current trial and in integrated safety results from the present and prior studies, phlebitis was more common with PG-BA diclofenac sodium. No cardiac or renal AEs or gastrointestinal bleeding were reported or observed. CONCLUSIONS: IV bolus HPbetaCD diclofenac sodium produced analgesia more quickly than, and with equal duration as, the 30-minute PG-BA diclofenac sodium infusion. Pooled data on thrombophlebitis from the present investigation and our prior studies of the novel formulation indicate this adverse effect is less frequent and less severe with HPbetaCD diclofenac sodium than with PG-BA diclofenac sodium.

mRNA deadenylation by PARN is essential for embryogenesis in higher plants.

Deadenylation of mRNA is often the first and rate-limiting step in mRNA decay. PARN, a poly(A)-specific 3' --> 5' ribonuclease which is conserved in many eukaryotes, has been proposed to be primarily responsible for such a reaction, yet the importance of the PARN function at the whole-organism level has not been demonstrated in any species. Here, we show that mRNA deadenylation by PARN is essential for viability in higher plants (Arabidopsis thaliana). Yet, this essential requirement for the PARN function is not universal across the phylogenetic spectrum, because PARN is dispensable in Fungi (Schizosaccharomyces pombe), and can be at least severely downregulated without any obvious consequences in Metazoa (Caenorhabditis elegans). Development of the Arabidopsis embryos lacking PARN (AtPARN), as well as of those expressing an enzymatically inactive protein, was markedly retarded, and ultimately culminated in an arrest at the bent-cotyledon stage. Importantly, only some, rather than all, embryo-specific transcripts were hyperadenylated in the mutant embryos, suggesting that preferential deadenylation of a specific select subset of mRNAs, rather than a general deadenylation of the whole mRNA population, by AtPARN is indispensable for embryogenesis in Arabidopsis. These findings indicate a unique, nonredundant role of AtPARN among the multiple plant deadenylases.