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Background: Elevated plasma ammonia is central to the pathogenesis of hepatic encephalopathy. Sodium phenylacetate or glycerol phenylbutyrate is approved for urea cycle disorders, but limited clinical data are available for hepatic encephalopathy. Phenylacetic acid (PAA) plasma exposure has been reported to correlate with neurologic adverse events in patients with cancer but not in patients with urea cycle disorders or hepatic encephalopathy. Ornithine phenylacetate, an intravenous dosage form of the L-ornithine salt of phenylacetate, is under development for hepatic encephalopathy., Objective: This analysis summarized the pharmacokinetics and safety of ornithine phenylacetate to support the dosing strategy and to assist with the monitoring and management of neurologic adverse events in a global clinical development program., Methods: Phenylacetic acid and phenylacetylglutamine (PAGN) pharmacokinetic data and adverse events from five clinical studies were included in the analysis. Hepatic and renal dysfunction were assessed by baseline Child-Pugh score and creatinine clearance, respectively. Predicted plasma exposures of PAA at the occurrence of neurologic adverse events were used for exposures and neurologic adverse event analysis., Results: Phenylacetic acid exhibited nonlinear pharmacokinetics. Phenylacetic acid exposure was 35% higher in Child-Pugh C than in Child-Pugh B. No significant pharmacokinetic difference was identified between Caucasian and Asian subjects after body weight adjustment. Phenylacetylglutamine renal clearance decreased by five-fold in severe renal impairment compared with subjects with normal renal function. Renal dysfunction significantly elevated PAGN plasma concentrations; however, elevated PAGN due to reduced excretion of PAGN did not change PAA exposure and plasma ammonia levels. No correlation was observed between PAA plasma exposure and neurologic adverse events in patients with stable cirrhosis or acute hepatic encephalopathy., Conclusions: Dose adjustment should be considered for patients with low body weight and severely impaired hepatic function. Phenylacetic acid plasma exposure was not correlated with neurologic adverse events in the ornithine phenylacetate target patient population., (© 2021. The Author(s).)

Postoperative antinociception control in fish is currently suboptimal, as commonly used antiinflammatory drugs last for only a few hours at tested temperatures. Therefore, long-acting anti-inflammatory drugs, such as robenacoxib, could improve the welfare of fish. The pharmacokinetics, duration of antinociceptive action, and potential adverse effects of robenacoxib were evaluated through two prospective randomized blinded trials in rainbow trout ( Oncorhynchus mykiss ). Six healthy rainbow trout received a single IM administration of robenacoxib (2 mg/kg), and two control fish received the same volume of saline IM. Blood samples were collected at predetermined time points for 5 d. Plasma robenacoxib concentrations were measured using high-performance liquid chromatography-high-resolution hybrid orbitrap mass spectrometry and noncompartmental pharmacokinetic analysis. Ten additional rainbow trout received an intralabial injection of 0.05 ml of 2% acetic acid following a previously validated nociceptive model. The treated group ( n = 6) received 2 mg/kg of robenacoxib IM and the control group ( n = 4) received an equivalent volume of saline IM. The behavior, appetite, and opercular rate of the fish were evaluated every hour for 5 h, then once daily for 3 d. All 12 treated trout and 6 controls underwent histopathologic evaluation. Average maximum plasma concentration ( C max ) was 329.9 ± 137.3 ng/ml observed at 2.1 ± 0.7 h ( T max ) and terminal half-life was 12.6 ± 2.27 h. Plasma concentrations described as antinociceptive in domestic carnivores were measured for 3-4 d. This dose was associated with a significant decrease in rocking behavior ( P = 0.017). No adverse effects were detected clinically nor on histopathology. Robenacoxib administered IM at 2 mg/kg appears to be safe and may provide an antinociceptive effect in rainbow trout. This study presents a new therapeutic option to provide long-lasting antinociception in rainbow trout.

Background: Robenacoxib (Onsior™) is a non-steroidal anti-inflammatory drug developed for canine and feline use for the control of pain and inflammation. It is available as both tablets and solution for injection. The objective of this study was to evaluate the safety of the interchangeable use of commercially available robenacoxib formulations when administered to cats orally using 6 mg tablets and subcutaneously using a solution for injection containing 20 mg/mL. Thirty-four naïve healthy 4-month old cats were enrolled in this 37-day study and were randomized to four groups (three robenacoxib and one control). One robenacoxib group received the maximum recommended dose (MRD) rate of each formulation, while the other two received two and three times this dose rate. The cats underwent three 10-day treatment cycles comprised of seven days of once daily oral administration followed by three days of subcutaneous administration. The third cycle was followed by an additional seven days of oral treatment. The control group received oral empty gelatin capsules or subcutaneous saline injections. Assessment of safety was based on general health observations, clinical observations, physical, ophthalmic, electrocardiographic and neurological examinations, clinical pathology evaluations, food consumption, body weight, and macroscopic and microscopic examinations. Blood samples were collected for toxicokinetic evaluation., Results: Blood concentrations of robenacoxib confirmed systemic exposure of all treated cats. All cats were in good health through study termination and there were no serious adverse events during the study. There were no changes in body weight, food consumption, ophthalmic, physical or neurological examinations during the study. Treatment-related abnormalities were of low occurrence at all doses and included injection site changes (transient edema with minimal or mild, subacute/chronic inflammation histologically) and prolongation of the QT interval. These findings were consistent with previously observed findings in studies with robenacoxib administered separately orally or subcutaneously in cats. Thus, there were no adverse effects that could be attributed specifically to the interchangeable use of oral and injectable robenacoxib., Conclusions: This 37-day laboratory study supports the safety of interchanging robenacoxib injection at a daily dose of 2 mg/kg with robenacoxib tablets at a daily dose of 1 mg/kg, or vice versa.

Tendinopathy is a rare but serious complication of quinolone therapy. Risk factors associated with quinolone-induced tendon disorders include chronic kidney disease accompanied by the accumulation of uremic toxins. Hence, the present study explored the effects of the representative uremic toxins phenylacetic acid (PAA) and quinolinic acid (QA), both alone and in combination with ciprofloxacin (CPX), on human tenocytes in vitro. Tenocytes incubated with uremic toxins +/- CPX were investigated for metabolic activity, vitality, expression of the dominant extracellular tendon matrix (ECM) protein type I collagen, cell-matrix receptor β1-integrin, proinflammatory interleukin (IL)-1β, and the ECM-degrading enzyme matrix metalloproteinase (MMP)-1. CPX, when administered at high concentrations (100 mM), suppressed tenocyte metabolism after 8 h exposure and at therapeutic concentrations after 72 h exposure. PAA reduced tenocyte metabolism only after 72 h exposure to very high doses and when combined with CPX. QA, when administered alone, led to scarcely any cytotoxic effect. Combinations of CPX with PAA or QA did not cause greater cytotoxicity than incubation with CPX alone. Gene expression of the pro-inflammatory cytokine IL-1β was reduced by CPX but up-regulated by PAA and QA. Protein levels of type I collagen decreased in response to high CPX doses, whereas PAA and QA did not affect its synthesis significantly. MMP-1 mRNA levels were increased by CPX. This effect became more pronounced in the form of a synergism following exposure to a combination of CPX and PAA. CPX was more tenotoxic than the uremic toxins PAA and QA, which showed only distinct suppressive effects.

Vicagrel is a new antiplatelet pro-drug based on clopidogrel sulfur lactone metabolites. The purpose of the study was to evaluate the safety, tolerability, and pharmacodynamics (PD) of vicagrel in healthy Chinese subjects.This study was designed as a single-center, randomized, double-blind, placebo-controlled, single oral ascending dose study. Fifty nine subjects were assigned to 6 vicagrel dose cohorts (5, 10, 20, 40, 60, and 75 mg), and 8 subjects were assigned to 75 mg clopidogrel. Within each vicagrel dose cohort, the 10 subjects (9 in the 75 mg cohort) were randomized 4:1 to receive vicagrel or placebo. Platelet function was assessed using VerifyNow P2Y12. ΔP2Y12 reaction units (ΔPRU) and percent inhibition platelet aggregation (%IPA) were used to evaluate the PD of vicagrel.Although the number of adverse events (AEs) increased with vicagrel dose, none were considered serious, suggesting that vicagrel is safe and well-tolerated. The ΔPRU and %IPA patterns suggest that inhibition of ADP-induced platelet aggregation increased in a dose-dependent manner across the 10 to 40 mg dose range. The inhibitory effect was nearly complete at 4 hours (mean %IPA 87.9%-93.0%, mean ΔPRU 206.6-240.0) for doses of 40 to 75 mg of vicagrel. In contrast, for 5 mg vicagrel and 75 mg clopidogrel, there were no measurable effects on platelet aggregation throughout the study.The results suggest that vicagrel at 40 to 75 mg inhibits ADP-induced platelet aggregation, with a fast onset of action and significantly greater potency than clopidogrel. These findings indicate that vicagrel may be a highly effective and well-tolerated antiplatelet agent.

Drug‑induced liver injury (DILI) is a common hepatic disease. The identification of biomarkers for DILI prediction is critical for rational drug use. The aim of the present study was to investigate liver injury caused by binaprofen and identify proteins that may serve as early biomarkers to predict DILI. For in vivo DILI assays, zebrafish were exposed to acetaminophen (APAP) and binaprofen for 12‑96 h before lethal concentration 50 (LC50), histopathological analysis, conventional and non‑conventional biomarker measurements were conducted. In vitro assays were performed in cultured liver cells; after 6‑24 h treatment with APAP and binaprofen the same measurements were conducted as aforementioned. The in vivo assays indicated that the LC50 of APAP was 5.2 mM, whereas the LC50 of binaprofen was 1.2 mM; 12‑48 h post‑treatment, liver cells exhibited mild to moderate vacuolization in a time‑ and concentration‑dependent manner in response to both drugs. During this time, conventional and non‑conventional biomarkers were also altered in a time‑ and concentration‑dependent manner; however, alterations in the levels of non‑conventional biomarkers occurred at an earlier time point compared with conventional biomarkers. The in vitro assays indicated that the half maximal inhibitory concentration (IC50) of APAP was 16.2 mM, whereas the IC50 of binaprofen was 5.3 mM; 12‑48 h post‑treatment, cultured liver cells exhibited mild to moderate swelling in a time‑ and concentration‑dependent manner. Alterations in the levels of conventional and non‑conventional biomarkers were similar to those observed in the in vivo assays. As a non‑steroidal anti‑inflammatory drug, binaprofen exhibited expected levels of liver toxicity in in vitro and in vivo assays, which were similar to APAP. Total bile acid and argininosuccinate lyase were identified as early biomarkers, which could accurately predict onset of binaprofen‑induced liver injury.

Background: Robenacoxib is a non-steroidal anti-inflammatory drug available for canine and feline use for the control of pain and inflammation marketed as Onsior™. The aim of this target animal safety study was to evaluate the 6-month safety profile of oral robenacoxib administration. It was a randomized, negative-controlled, parallel group study. Thirty-two healthy, young, experimentally naïve, purebred Beagle dogs were administered 0 (sham control, Group 1), 2, 6, and 10 mg/kg robenacoxib (corresponding to the upper end of the dosage range [1X, Group 2] and multiples thereof [3X and 5X, Group 3 and 4]), orally once daily for 6 months. Assessment of safety included general health and clinical observations, physical, neurological, ophthalmological and electrocardiographic examinations, gross and histopathological examinations and clinical pathology evaluations. Blood samples were collected for toxicokinetic assessment of robenacoxib., Results: No serious adverse events were reported. When compared with control, no treatment effect was observed for body weight, feed or water consumption, clinical pathology, urinalysis and fecal examination parameters. There were no treatment-related changes in stifle joint tissues and microscopic/histopathology examinations of all tissues/organs were normal. Salivation and soft feces were noted in all groups but observed more frequently in the treated groups as compared with control. On Day 178, increased buccal mucosal bleeding times were observed in two treated animals (Group 3 and 4) and one dog in Group 4 displayed a retinal change. Decreased hopping and conscious proprioception was noted in four treated dogs. One dog in Group 2 had ventricular premature complexes. Post-mortem changes included mild, red foci on the cecum in one dog (Group 3) and minimal duodenal discoloration in one dog (Group 4), with no corresponding histological findings in either dog. Ovarian weights were decreased in females from Group 3 and 4 with no gross or histological changes in the ovaries. Blood concentrations of robenacoxib confirmed systemic exposure of treated dogs. Exposure increased with increasing doses and there were no accumulation of robenacoxib in blood., Conclusions: Robenacoxib was well tolerated at doses from 2 to 10 mg/kg/day and this 6-month study supports the safe use of Onsior™ (robenacoxib) tablets in dogs for the intended dosing regimen.

Purpose: To test the intracameral safety of nepafenac and its efficacy in inhibiting prostaglandin synthesis during phacoemulsification surgery., Methods: The safety evaluation was conducted in normal eyes of rabbits, 0.1ml of 0.3% and 1% nepafenac was injected intracamerally. Extensive studies to detect adverse response ranged from a gross examination of eyes under slit lamp biomicroscope, fluorescein dye test, Schirmer tear test, test for corneal sensitivity, intraocular pressure measurement (IOP), specular microscopy, electroretinography(ERG), and histopathological examination of intraocular tissues. Efficacy of nepafenac was studied by intracameral injection of 0.1%, 0.3% nepafenac, nepafenac 0.3%+1% lignocaine, and 1% lignocaine alone, before phacoemulsification surgery and intraoperative mydriasis along with PGE2(ProstaglandinE2) secretion were recorded., Results: Single 0.1ml of 0.3% or 1% nepafenac did not significantly (p > 0.05) alter physiological parameters and histology of cornea, iris, and retina. Nepafenac 0.3% effectively inhibited PGE2 secretion. No significant (p > 0.05) prevention of miosis was recorded with 0.1% or 0.3% nepafenac. However, a combination of 0.3% nepafenac + 1% lignocaine and 1% lignocaine alone significantly (p < 0.05) arrested miosis during the intraoperative period., Conclusion: An intracameral concentration of up to 1% nepafenac does not adversely affect the rabbit eye. Nepafenac fails to prevent miosis but inhibits prostaglandin release during phacoemulsification surgery.

Background: Robenacoxib (Onsior™) is a non-steroidal anti-inflammatory drug developed for canine and feline use for the control of pain and inflammation. It is available as both tablets and solution for injection. The objective of this safety study was to investigate the interchangeable use of two robenacoxib formulations in dogs using a novel study design alternating between oral tablets and subcutaneous injections. Thirty-two naïve healthy 4-month dogs were enrolled in this 88-day study and were randomized among four groups to be untreated or to receive robenacoxib at the highest recommended or elevated dose rates. The dogs were administered three 20-day treatment cycles each separated by a 14-day washout period. Each 20-day cycle was comprised of 10 days of once daily oral administration, 3 days of subcutaneous administration, followed by further 7 days of oral administration (Groups 2 to 4). The control group (Group 1) received oral empty gelatin capsules or subcutaneous saline injections. Assessment of safety was based on general health observations, clinical observations, physical and neurological examinations including ophthalmological examinations, electrocardiographic examinations and clinical pathology evaluations, food and water consumption, body weight, and macroscopic and microscopic examinations. Blood samples were collected for pharmacokinetic evaluation., Results: Blood concentrations of robenacoxib confirmed systemic exposure of all treated dogs. All dogs were in good health through study termination and there were no serious adverse events during the course of the study. No changes in body weight, food consumption, ophthalmic, neurological examinations, electrocardiograms, buccal mucosal blood times, clinical pathology or organ weight were attributable to robenacoxib formulation administration. Primary treatment-related abnormalities were of low incidence at all doses. They were confined to macroscopic and microscopic changes observed locally at the subcutaneous injection sites and microscopic findings within the gastrointestinal tract. These findings were as expected based on previous studies with robenacoxib solution for injection alone and the known properties of this class of compound and mode of administration. There were no adverse effects which could be attributed specifically to the interchangeable use of oral and injectable robenacoxib., Conclusions: Alternating regimens of robenacoxib tablets and solution for injection were well tolerated in healthy young dogs.

Urea cycle enzyme deficiency (UCED) patients with hyperammonemia are treated with sodium benzoate (SB) and sodium phenylacetate (SPA) to induce alternative pathways of nitrogen excretion. The suggested guidelines supporting their use in the management of hyperammonemia are primarily based on non-analytic studies such as case reports and case series. Canine congenital portosystemic shunting (CPSS) is a naturally occurring model for hyperammonemia. Here, we performed cross-over, randomized, placebo-controlled studies in healthy dogs to assess safety and pharmacokinetics of SB and SPA (phase I). As follow-up safety and efficacy of SB was evaluated in CPSS-dogs with hyperammonemia (phase II). Pharmacokinetics of SB and SPA were comparable to those reported in humans. Treatment with SB and SPA was safe and both nitrogen scavengers were converted into their respective metabolites hippuric acid and phenylacetylglutamine or phenylacetylglycine, with a preference for phenylacetylglycine. In CPSS-dogs, treatment with SB resulted in the same effect on plasma ammonia as the control treatment (i.e. saline infusion) suggesting that the decrease is a result of volume expansion and/or forced diuresis rather than increased production of nitrogenous waste. Consequentially, treatment of hyperammonemia justifies additional/placebo-controlled trials in human medicine.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) have been proven to be effective in controlling peri-operative pain in dogs. Robenacoxib is an NSAID with high selectivity for the cyclooxygenase (COX)-2 isoform. The objective of this study was to assess the efficacy and safety of an oral tablet formulation of robenacoxib in client-owned dogs undergoing soft tissue surgery. The study was a prospective, multi-center, randomized, masked, placebo-controlled, parallel-group clinical trial. A total of 239 dogs were included and randomly allocated in a 1:1 ratio to receive either robenacoxib or placebo. Each dog received an oral tablet administration of either robenacoxib, at a target dose of 2 mg/kg, or placebo once prior to surgery and for two additional days post-operatively. All dogs also received a pre-anesthetic dose of 0.2 mg/kg butorphanol (intravenous or intramuscular). Pain assessments were performed using the short form of the Glasgow Composite Measure Pain Scale. Robenacoxib was compared to the placebo group on a success/failure basis. Treatment failure was defined as the need for rescue therapy to control post-operative pain., Results: Significantly (P = 0.019) more dogs administered robenacoxib were considered treatment successes (89 of 116, 76.72%) compared to dogs given placebo (74 of 115, 64.35%). The percentage of treatment failure was therefore 23.28% in the robenacoxib and 35.65% in the placebo group. The least squares mean total pain scores were significantly different between groups and in favor of robenacoxib at 3 and 5 hours (P < 0.05) and 8 hours post-extubation (P < 0.01). Pain at the surgery sites (response to touch) was also significantly improved at 3, 5 and 8 hours post-extubation in dogs receiving robenacoxib versus placebo (P < 0.01). In addition, a significant overall improvement in posture/activity was revealed with robenacoxib having lower scores versus placebo (P < 0.01). No significant differences between the robenacoxib and placebo groups in the frequency of reported adverse events were observed., Conclusions: Robenacoxib by oral (tablet) administration was effective and well tolerated in the control of peri-operative pain and inflammation associated with soft tissue surgery in dogs.

Purpose: To demonstrate the efficacy and safety of once-daily nepafenac 0.3% ophthalmic suspension versus vehicle, based on clinical outcomes, after cataract surgery in patients with diabetes., Design: Two prospective, randomized, multicenter, double-masked, vehicle-controlled phase 3 studies., Participants: Total, 615 patients in study 1 and 605 patients in study 2., Methods: Patients were randomized (1:1) to topical nepafenac 0.3% or vehicle once-daily starting the day before surgery and continuing for 90 days thereafter., Main Outcome Measures: Key efficacy variables were: patients (%) in whom macular edema (ME) developed (≥30% increase from preoperative baseline central subfield macular thickness) within 90 days after cataract surgery and the patients (%) with a best-corrected visual acuity (BCVA) improvement of ≥15 letters from preoperative baseline through day 14 maintained through day 90. Secondary end points included: patients (%) with a BCVA improvement of ≥15 letters from preoperative baseline through days 90 and 60 and safety over 3 months., Results: A significantly lower percentage of patients demonstrated ME within 90 days after surgery with nepafenac 0.3% versus vehicle (study 1: 2.3% vs. 17.3%; P < 0.001; study 2: 5.9% vs. 14.3%; P = 0.001; pooled: 4.1% vs. 15.9%; P < 0.001). The percentage of patients achieving a ≥15-letter improvement from baseline through day 14 maintained through day 90 with nepafenac 0.3% versus vehicle was 61.7% versus 43.0% (P < 0.001) in study 1, 48.8% versus 50.5% (P = 0.671) in study 2, and 55.4% versus 46.7% (P = 0.003) in the pooled analysis. A greater percentage of patients treated with nepafenac 0.3% versus vehicle in study 1 and similar percentage in study 2 had a BCVA improvement of ≥15 letters from preoperative baseline through day 90 (77.2% vs. 67.7% [P = 0.009] and 65.4% vs. 65.9% [P = 0.888]) and through day 60 (76.2% vs. 64.7% [P = 0.002] and 68.9% vs. 62.1% [P = 0.092]). No unanticipated adverse events were observed., Conclusions: These studies demonstrated the clinical benefits of nepafenac 0.3% over vehicle in reducing the risk of postoperative ME, with the integrated analysis showing improved BCVA after cataract surgery in patients with diabetic retinopathy, with no unanticipated safety events., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are used routinely to control pain and inflammation after surgery in dogs. Robenacoxib is a cyclooxygenase-2 selective NSAID., Hypothesis/objective: Assess the clinical efficacy and safety of an injectable formulation of robenacoxib in dogs undergoing surgery., Animals: Three hundred and seventeen client-owned dogs (N = 159 robenacoxib or N = 158 placebo)., Methods: In this prospective, multicenter, randomized, masked, placebo-controlled, parallel-group study, dogs received a SC injection of either robenacoxib, at a target dose of 2.0 mg/kg, or placebo once prior to surgery and for 2 additional days postoperatively. Pain assessments were performed using the short form of the Glasgow Composite Measure Pain Scale (CMPS-SF). The primary efficacy variable was treatment success/failure, with failure defined as the need for rescue therapy to control pain or withdrawal of the dog from the study due to an adverse event., Results: Significantly (P = .006) more dogs administered robenacoxib were considered treatment successes (108 of 151, 73.7%) compared to dogs given placebo (85 of 152, 58.1%). Total pain scores (P < .01), pain at the surgery sites (response to touch, P < .01), and posture/activity (P < .05) were significantly improved at 3, 5, and 8 hours postextubation in dogs receiving robenacoxib versus placebo., Conclusions and Clinical Importance: Robenacoxib administered by SC injection prior to surgery and for 2 additional days postoperatively was effective and well tolerated in the control of postoperative pain and inflammation associated with soft tissue surgery in dogs., (Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

As a new ophthalmic non-steroidal anti-inflammatory drug (NSAID) with prodrug structure, Nepafenac was supposed to have a better efficacy than conventional NSAIDs both in patients' tolerability and ocular inflammation associated with cataract surgery. However, many current studies reached contradictory conclusions on the superiority of Nepafenac over Ketorolac. The objective of our study is to evaluate the efficacy and patients' tolerability of Nepafenac and Ketorolac following cataract surgery. To clarify this, we conducted a meta-analysis of randomized controlled trials. Eleven articles were included in this study. The dataset consisted of 1165 patients, including 1175 cataract surgeries. Among them, 574 patients were in the Nepafenac group and 591 in the Ketorolac group. Our analysis indicated that these two drugs were equally effective in controlling post cataract surgery ocular inflammation, reducing macular edema, achieving a better visual ability and maintaining intraoperative mydriasis during cataract surgery. However, Nepafenac was more effective than Ketorolac in reducing the incidence of postoperative conjunctival hyperemia and ocular discomfort. This meta-analysis indicated that topical Nepafenac is superior to Ketorolac in patients' tolerability following cataract surgery. However, these two drugs are equally desirable in the management of anterior chamber inflammation, visual rehabilitation and intraoperative mydriasis. Given the limitations in our study, more researches with larger sample sizes and focused on more specific indicators such as peak aqueous concentrations of drugs or PEG2 levels are required to reach a firmer conclusion.

Objective: Arhalofenate (ARH), in development for gout, has uricosuric and anti-flare activities. ARH plus febuxostat (FBX) were evaluated in subjects with gout for serum uric acid (SUA) lowering, drug interaction, and safety., Methods: Open phase II trial in gout volunteers (NCT02252835). Cohort 1 received ARH 600 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 80 mg followed by 40 mg. FBX 40 mg was continued alone for 2 weeks. Cohort 2 received ARH 800 mg for 2 weeks, followed by sequential 1-week co-administration of FBX 40 mg followed by 80 mg. FBX 80 mg was continued alone for 2 weeks. SUA, its fractional excretion (FEUA), and plasma oxypurines were assessed. Pharmacokinetics of FBX and ARH were determined alone and in combination for cohort 2., Results: Baseline mean SUA was 9.4 mg/dl for cohort 1 (n = 16) and 9.2 mg/dl for cohort 2 (n = 16). The largest SUA decrease (63%) was observed with ARH 800 mg + FBX 80 mg, with all subjects reaching SUA < 6 mg/dl and 93% < 5 mg/dl. The area under the curve (AUC) (0-t) of ARH acid + FBX/ARH acid was 108%. The AUC (0-t) of FBX + ARH acid/FBX was 87%. As expected, FBX increased oxypurines and increases were unaffected by ARH co-administration. Baseline FEUA were low (3.5%-4.6%) and ARH increased them toward normal without overexcretion of UA. ARH was well tolerated and appeared safe., Conclusion: ARH and FBX lowered SUA by complementary mechanisms. The combination provided greater decreases than each drug alone. The combination was well tolerated and appeared safe., Trial Registration: NCT02252835.

Purpose: Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the prevention and treatment of inflammation and pain following cataract surgery. Preservative-free diclofenac and nepafenac drops are commonly used ophthalmic NSAIDs. The purpose of this study was to compare the tolerability of diclofenac to that of nepafenac., Methods: In this prospective patient-blinded study, consecutive patients undergoing cataract surgery were included. One drop of nepafenac 0.1% and diclofenac sodium 0.1% were instilled in the right and left eyes, respectively, one immediately after the other, 1 day before surgery. Visual analog scale (scale 0-10) was used to measure patient discomfort, itching, burning, and pain at 1 second (s), 15 s, 1 minute (min), and 5 min postadministration., Results: Overall, 44 eyes of 22 patients were included in this study. Diclofenac and nepafenac had high and similar tolerability at all time points with no significant difference regarding all aspects of tolerability. A vast majority of patients (72%) did not prefer 1 drop over the other in terms of overall comfort., Conclusions: Both diclofenac and nepafenac seem to have similar high tolerability. Diclofenac may be an affordable alternative to nepafenac and therefore should be considered by prescribing physicians, specifically in preoperative cataract patients.

Objectives: The objective of this study was to evaluate the clinical safety of the non-steroidal anti-inflammatory drug (NSAID) robenacoxib in cats with osteoarthritis. Degenerative joint disease, including osteoarthritis, is highly prevalent in cats and many cases have associated pain and impaired mobility. Although NSAIDs are used routinely to control pain and inflammation in cats with osteoarthritis, there are safety concerns because of the high concurrent prevalence of chronic kidney disease (CKD) and the paucity of data on the safety of these drugs in target clinical populations., Methods: A total of 194 cats with osteoarthritis were recruited and randomly allocated to receive either robenacoxib at a dosage of 1.0-2.4 mg/kg (n = 95) or placebo (n = 99) tablets PO q24h for 28 days. Safety was assessed in 193 cats, including a subgroup of 40 animals with concurrent CKD, defined as serum creatinine concentration ⩾1.6 mg/dl and urine specific gravity <1.030. Safety endpoints included reports of adverse events, results of clinical examinations, including body weight, and clinical chemistry and hematology variables., Results: In all 193 cats and the subgroup of 40 animals with concurrent CKD, there were no differences between groups in frequencies of reported adverse events, body weight change or results of serum or urine chemistry or hematology variables., Conclusions and Relevance: Robenacoxib was well tolerated when administered daily for 1 month in cats with osteoarthritis, including cats with evidence of concurrent CKD. There was no clinical indication of damage to the gastrointestinal tract, kidney or liver., (© ISFM and AAFP 2015.)

Objective: Arhalofenate is a novel antiinflammatory uricosuric agent. The objective of this study was to evaluate its antiflare activity in patients with gout., Methods: This was a 12-week, randomized, double-blind, controlled phase IIb study. Eligible patients had had ≥3 flares of gout during the previous year, had discontinued urate-lowering therapy and colchicine, and had a serum uric acid (UA) level of 7.5-12 mg/dl. Patients were randomly assigned at a 2:2:2:2:1 ratio to receive 600 mg arhalofenate, 800 mg arhalofenate, 300 mg allopurinol, 300 mg allopurinol plus 0.6 mg colchicine, or placebo once a day. The primary outcome measure was the flare incidence (number of flares divided by time of exposure). The serum UA level was a secondary outcome measure., Results: A total of 239 gout patients were randomized and took at least 1 dose of study medication. The primary outcome measure comparing flare incidence between 800 mg arhalofenate and 300 mg allopurinol was achieved, with a 46% decrease in the 800 mg arhalofenate group (0.66 versus 1.24; P = 0.0056). Treatment with 800 mg arhalofenate was also significantly better than placebo (P = 0.049) and not significantly different from treatment with 300 mg allopurinol plus 0.6 mg colchicine (P = 0.091). Mean changes in serum UA level were -12.5% with 600 mg arhalofenate and -16.5% with 800 mg arhalofenate (P = 0.001 and P = 0.0001, respectively, versus -0.9% with placebo). There were no meaningful differences in adverse events (AEs) between groups, and there were no serious AEs related to arhalofenate. Urinary calculus occurred in 1 patient receiving 300 mg allopurinol. No abnormal serum creatinine values >1.5-fold the baseline value were observed in the arhalofenate-treated groups., Conclusion: Arhalofenate at a dosage of 800 mg decreased gout flares significantly compared to allopurinol at a dosage of 300 mg. Arhalofenate was well tolerated and appeared safe. Arhalofenate is the first urate-lowering antiflare therapy., (© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Purpose of Review: Toll-like receptors (TLRs) are novel and promising targets for allergen immunotherapy. Bench studies suggest that TLR agonists reduce Th2 responses and ameliorate airway hyper-responsiveness. In addition, clinical trials are at initial phases to evaluate the safety and efficacy of TLR agonists for the allergen immunotherapy of patients with allergic rhinitis and asthma. (Figure is included in full-text article.), Recent Findings: To date, two allergy vaccine-containing TLR agonists have been investigated in clinical trials; Pollinex Quattro and AIC. The former contains monophosphoryl lipid, a TLR4 agonist and the latter contains, CpG motifs activating the TLR9 cascade. Preseasonal subcutaneous injection of both of these allergy vaccines has been safe and efficacious in control of nasal symptoms of patients with allergic rhinitis. CRX-675 (a TLR4 agonist), AZD8848 (a TLR7 agonist), VTX-1463 (a TLR8 agonist) and 1018 ISS and QbG10 (TLR9 agonists) are currently in clinical development for allergic rhinitis and asthma., Summary: TLR agonists herald promising results for allergen immunotherapy of patients with allergic rhinitis and asthma. Future research should be directed at utilizing these agents for immunotherapy of food allergy (for instance, peanut allergy) as well.

Background: AZD3043 is a positive allosteric modulator of the γ-aminobutyric acid type A receptor that is rapidly metabolized to an inactive metabolite by esterases present in blood and liver. Preclinical results suggest that AZD3043 has the potential as a short-acting IV sedative/anesthetic drug with rapid and predictable recovery characteristics and a favorable safety and tolerability profile., Methods: Our primary objective in this phase 1, single-center, open-label study was to evaluate the safety and tolerability of AZD3043 after IV infusion and to estimate the maximal tolerated dose. Secondary objectives included the evaluation of AZD3043 pharmacokinetics, pharmacodynamics, and efficacy. Sequential ascending-dose cohorts of 5 or 6 healthy male volunteers aged 18 to 45 years received a single 30-minute IV infusion of AZD3043. Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index., Results: Fifty-three subjects received AZD3043 in infusion rate cohorts of 1, 3, 6, 12, 18, 27, 36, 54, and 81 mg/kg/h. There were no discontinuations, and dose escalation was stopped on reaching the predefined exposure limit. Adverse events occurring in >1 subject were headache (n = 4), erythema (n = 3), chest discomfort (n = 2), nausea (n = 2), and dyspnea (n = 2). The frequency and character of adverse events appeared unrelated to dose. There were no spontaneous reports of pain on injection and no clinically relevant changes in respiratory rate or arterial blood pressure. However, heart rate increased dose-dependently at infusion rates >18 mg/kg/h. Occurrence of sedation/anesthesia corresponded with dose; the lowest applied infusion rate to induce anesthesia according to clinical signs of sedation/anesthesia at predefined time points was 12 mg/kg/h (1 of 6 subjects anesthetized), and all subjects in the 3 highest dose groups were anesthetized. The onset of anesthesia ranged from 4 minutes in the highest infusion rate group to 29 minutes in the 12-mg/kg/h infusion rate group. Return of response to oral command occurred at 3 minutes after the end of infusion in the single subject who was anesthetized in the 12-mg/kg/h group and median 25 minutes in the 81-mg/kg/h group. Involuntary movements ranging from minor twitches to extensive movements were accompanied by increased muscle tone., Conclusions: AZD3043 was well tolerated in this first human study and seems to exhibit rapid onset and recovery, indicating potential use as a short-acting drug for anesthesia and sedation.

Background: AZD3043 (THRX-918661) is an investigational phenylpropanoid sedative/anesthetic that is rapidly metabolized by esterases in blood and liver. In the first-in-man study, a 30-minute constant IV infusion of AZD3043 induced anesthesia without major safety or tolerability concerns and with rapid recovery characteristics., Methods: The primary objective of this phase 1, single-center, open-label study (clinicaltrials.gov NCT00984880) was to evaluate the safety and tolerability of AZD3043 administered as a single IV bolus and as a bolus followed by infusion. Secondary objectives included evaluation of AZD3043 pharmacodynamics and efficacy. Sequential ascending dose cohorts of 8 healthy volunteers aged 18 to 65 years received either a single 1-minute bolus IV infusion (part A) or a 1-minute bolus followed by a 30-minute infusion (part B). Assessments included adverse events, vital signs, blood gases, laboratory values, clinical signs of sedation/anesthesia, and bispectral index score., Results: Seventy-two subjects (8 females, 64 males) received AZD3043 doses of 1, 1.5, 2, 4, and 6 mg/kg bolus over 1 minute (part A) or 0.8 + 10, 1 + 15, 3 + 30, and 4 + 40 mg/kg bolus + mg/kg/h infusion for 30 minutes (part B). There were no discontinuations. Adverse events occurring in >1 subject were headache (n = 15; 21%), nausea (n = 7; 10%), vomiting (n = 3; 4%), and fatigue (n = 2; 3%). Twenty-one subjects experienced at least 1 adverse event. There seemed to be no dose relationship associated with any adverse event. Ventilation was maintained, but there was a dose-dependent increase in heart rate. There were no spontaneous reports of pain on injection. Thirty-two subjects were anesthetized, including all subjects in the highest dose group in part A and all subjects in the 2 highest dose groups in part B. Recovery from anesthesia was rapid, with swift return of orientation and proprioception. All subjects were able to walk 10 m without support at their first assessment, 30 minutes after end of dosing, except for 1 subject in each of the 2 mg/kg bolus (part A) and 4 mg/kg bolus + 40 mg/kg/h 30-minute infusion (part B) dose groups, who passed this test at the subsequent assessment, 45 minutes after the end of dosing. Involuntary movements were observed at higher doses, accompanied by increased muscle tone., Conclusions: AZD3043 provided rapid recovery from anesthesia with maintained ventilation. Further studies are warranted in a clinical setting.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in veterinary medicine. Robenacoxib is a NSAID with high selectivity for the cyclo-oxygenase-2 enzyme. In this study, the efficacy and safety of robenacoxib were evaluated in a prospective, randomised, active- and placebo-controlled masked clinical trial in 147 cats undergoing orthopaedic surgery. Cats were randomised into two treatment groups: Group 1, robenacoxib (2 mg/kg) administered via subcutaneous (s.c.) injection before surgery, followed by robenacoxib tablets (1-2.4 mg/kg) administered post-operatively for approximately 9 days (n = 101) and Group 2, meloxicam (0.3 mg/kg) administered s.c. before surgery, followed by placebo tablets administered post-operatively for approximately 9 days (n = 46). Cats were assessed using numerical rating scales (NRSs) by clinicians before surgery and at 3, 8, 22 and 28 hours after surgery and at the final visit (VF on approximately Day 10), and daily by their owners from Day 1 to the VF., Results: The primary end point was the global investigator score which was the sum of clinician NRSs for posture, behaviour and pain on palpation/manipulation. The efficacy of the single robenacoxib injection, assessed during 3 to 22 hours, was statistically non-inferior to meloxicam, with a relative efficacy of 1.029 (95% confidence interval, 0.847-1.231). No significant differences were detected during the follow-up treatment with robenacoxib tablets for approximately 9 days compared with placebo via clinician assessments at 28 hours and the VF, or in owner assessments on Days 1-VF. There were no significant differences in frequencies of reported adverse events, clinical observations and haematology or clinical chemistry variables between the groups., Conclusions: Single s.c. injection of robenacoxib before surgery had non-inferior efficacy compared with meloxicam in controlling post-operative pain and inflammation in cats undergoing orthopaedic surgery. Follow-up treatment with oral robenacoxib tablets for approximately 9 days was well tolerated, but there were no differences in the efficacy scores after Day 1 compared with the group receiving meloxicam s.c. followed by placebo control.

Tectal glioma is a midbrain tumor. The patient generally presents with symptoms related to increased intracranial pressure and requires treatment for hydrocephalus. No effective pharmacological treatments have yet been introduced. This report discusses a case of a 13-year-old male diagnosed with tectal glioma who obtained a complete response and long-term survival after the treatment with antineoplastons (ANP) in phase II trial. Prior treatment consisted of placement of a ventriculoperitoneal shunt. After 6 years of stabilization there had been an increase in tumor size with signs of malignant transformation. The patient received treatment with ANP A10 and AS2-1 infusions for 20 months, obtained a complete response, and was switched to maintenance with ANP capsules. All treatments were discontinued in December 2003. Adverse events according to CTCAE v3.0 included: hypernatremia (two events of grade 3, one event of grade 2, four events of grade 1), one case of fatigue (grade 2), and one allergic reaction (grade 1). Currently, over 20 years from his diagnosis and over 13 years from treatment start he is symptom-free and leads a normal life. This report indicates that it is possible to obtain long-term survival of a child with tectal glioma with currently available investigational treatment., (© 2015 S. Karger AG, Basel.)

Unlabelled: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in animals, especially in dogs, to manage pain due to inflammatory disease. This study investigated whether plant drugs can prevent mucosal injury induced by robenacoxib. We used fifteen healthy beagle dogs (7 male and 8 female) aged 4 months, weighing 4.2-5.1 kg at the beginning of the study. Endoscopy and biopsy of the colon were performed before and on the 21 day treatment with robenacoxib (1), robenacoxib, herbal solution with liquorice extract (2), placebo - an empty capsule (3). There were 5 animals in each group. The greatest microscopic damage in the colon was observed in animals which received robenacoxib. Plant drug administration reduced the severity of lesions in the colon when administered with robenacoxib (ARI = - 0.15)., Conclusion: concurrent administration of liquorice extract and plant solution with robenacoxib was associated with significant decreased severity of the robenacoxib-induced colonic mucosal lesions.

Background: Brainstem gliomas (BSG) are relatively rare tumors of which recurrent pediatric diffuse intrinsic pontine gliomas (RPDIPG) comprise a distinct group. Numerous trials have been conducted on RPDIPG, none of which have resulted in identifying any proven pharmacological treatment benefit. This study included 40 patients diagnosed with different types of BSG, but it was decided to describe first the encouraging results in the most challenging group of RPDIPG., Materials and Methods: This single-arm phase II study evaluated the efficacy and safety of the combination of antineoplastons A10 and AS2-1 (ANP) in patients with RPDIPG. Seventeen patients (median age 8.8 years) were enrolled, and all were diagnosed with RPDIPG. ANP was administered intravenously daily. Efficacy analyses were conducted in this group of patients., Results: In this group, complete responses were observed in 6 % of patients, partial responses in 23.5 %, and stable disease in 11.8 %. Six-month progression-free survival was 35.3 %. One-year overall survival was 29.4 %, 2 years 11.8 %, and 5, 10, and 15 years 5.9 %. One patient with DIPG is alive over 15 years post-treatment. Grade 3 and higher toxicities including hypokalemia and fatigue occurred in 6 %, hypernatremia in 18 %, fatigue and urinary incontinence in 6 %, and somnolence in 12 %. In a single patient, grade 4 hypernatremia occurred when he was on mechanical ventilation. He was disconnected from the ventilator and died from brain tumor according to the attending physician. Responding patients experienced improved quality of life., Conclusion: The results suggest that ANP shows efficacy and acceptable tolerability profile in patients with RPDIPG.

Background: The D-prostanoid receptor and the chemoattractant receptor homologous molecule expressed on T(H)2 cells (CRTH2) are implicated in asthma pathogenesis. AMG 853 is a potent, selective, orally bioavailable, small-molecule dual antagonist of human D-prostanoid and CRTH2., Objective: We sought to determine the efficacy and safety of AMG 853 compared with placebo in patients with inadequately controlled asthma., Methods: Adults with moderate-to-severe asthma were randomized to placebo; 5, 25, or 100 mg of oral AMG 853 twice daily; or 200 mg of AMG 853 once daily for 12 weeks. All patients continued their inhaled corticosteroids. Long-acting β-agonists were not allowed during the treatment period. Allowed concomitant medications included short-acting β-agonists and a systemic corticosteroid burst for asthma exacerbation. The primary end point was change in total Asthma Control Questionnaire score from baseline to week 12. Secondary and exploratory end points included FEV(1), symptom scores, rescue short-acting β-agonist use, and exacerbations., Results: Among treated patients, no effect over placebo (n = 79) was observed in mean changes in Asthma Control Questionnaire scores at 12 weeks (placebo, -0.492; range for AMG 853 groups [n = 317], -0.444 to -0.555). No significant differences between the active and placebo groups were observed for secondary end points. The most commonly reported adverse events were asthma, upper respiratory tract infection, and headache; 9 patients experienced serious adverse events, all of which were deemed unrelated to study treatment by the investigator., Conclusion: AMG 853 as an add-on to inhaled corticosteroid therapy demonstrated no associated risks but was not effective at improving asthma symptoms or lung function in patients with inadequately controlled moderate-to-severe asthma., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Phosphodiesterase 4 (PDE4) inhibitors have been developed for the treatment of pulmonary inflammatory diseases, but their clinical use was dose-limited by mainly gastric adverse effects. Recent studies suggested PDE4B-selective inhibitors over PDE4D are supposed to display a wider therapeutic index than subtype non-selective PDE4 inhibitors such as roflumilast. Compound A was identified as an orally active PDE4B-selective inhibitor over PDE4D both in humans (80-fold selective) and mice (29-fold selective). In this study, the therapeutic effects of compound A and roflumilast were evaluated on lipopolysaccaride (LPS) injection-induced plasma TNF-α elevation and on LPS inhalation-induced pulmonary neutrophilia in mice. The inhibitory effect on gastric emptying in mice was evaluated as a gastric adverse effect. The therapeutic index for TNF-α production (TI(TNF) = ID50 in gastric emptying / ID50 in LPS injection-induced plasma TNF-α elevation) of compound A was larger than roflumilast (9.0 and 0.2, respectively), whereas the therapeutic index for pulmonary neutrophilia (TI(Neu) = ID50 in gastric emptying / ID50 in LPS inhalation-induced pulmonary neutrophilia) of compound A was comparable to roflumilast (1.0 and 0.5, respectively). In conclusion, the TI(Neu) of compound A was not superior compared to that of roflumilast in spite of its high selectivity for PDE4B over PDE4D in mice.

The prostaglandin D(2) receptor type 2 (DP2) and its ligand, PGD(2), have been implicated in the development of asthma and other inflammatory diseases. The authors evaluated the pharmacodynamics, pharmacokinetics and safety of [2'-(3-benzyl-1-ethyl-ureidomethyl)-6-methoxy-4'-trifluoromethyl-biphenyl-3-yl]-acetic acid sodium salt (AM211), a novel and potent DP2 antagonist, in healthy participants. Single and multiple doses of AM211 demonstrated dose-dependent inhibition of eosinophil shape change in blood with near-complete inhibition observed at trough after dosing 200 mg once daily for 7 days. Maximum plasma concentrations and exposures of AM211 increased in a greater-than-dose-proportional manner after single and multiple dosing. After multiple dosing, the exposures on day 7 were higher than on day 1 with accumulation ratio values ranging from 1.4 to 1.5. Mean terminal half-life values ranged from 14 to 25 hours across the dose range of 100 to 600 mg. AM211 was well tolerated at all doses in both the single- and multiple-dose cohorts. These data support additional clinical studies to evaluate AM211 in asthma and other inflammatory diseases.

Purpose: To evaluate the efficacy of prophylactic ketorolac 0.5% versus nepafenac 0.1% versus placebo on macular volume 1 month after uneventful phacoemulsification and evaluate the health-related quality-of-life (HRQOL) of topical nonsteroidal antiinflammatory drugs (NSAIDs) in the context of cataract surgery., Setting: Hotel Dieu Hospital, Kingston, Ontario, Canada., Design: Prospective placebo-controlled parallel-assignment double-masked randomized clinical trial., Methods: In this study, patients 18 years or older scheduled for routine phacoemulsification were randomized to a placebo, ketorolac 0.5%, or nepafenac 0.1% and dosed 4 times a day starting 1 day before surgery and continuing for 4 weeks. Spectral-domain macular cube ocular coherence tomography scans measuring central subfield thickness, macular cube volume, and average macular cube thickness were performed at baseline and 1 month postoperatively. The HRQOL metrics were determined with the Comparison of Ophthalmic Medications for Tolerability (COMTOL) questionnaire., Results: Each study group comprised 54 patients. One month postoperatively, although a trend toward significance occurred for nepafenac and ketorolac, analysis of the means of differences showed no statistically significant differences between the 3 study groups (P=.2901). The COMTOL analysis found no difference in tolerability, compliance, side-effect frequency and bother, and effects on HRQOL between ketorolac and nepafenac compared with the placebo., Conclusions: One month after uneventful phacoemulsification, there was no difference in macular volume between the placebo, ketorolac, and nepafenac. Ketorolac and nepafenac were well tolerated with minimal side-effect profiles. Thus, for patients without risk factors having routine surgery, prophylactic topical NSAIDs are not recommended., (Copyright © 2012 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

The objective of the study was to evaluate the efficacy and tolerability of robenacoxib, a selective cyclooxygenase-2 inhibitor, for the treatment of acute pain and inflammation associated with musculoskeletal disorders in cats. The study was a prospective, multi-centre, randomised, blinded, non-inferiority design clinical trial comparing robenacoxib to ketoprofen. A total of 68 cats presenting with pain and inflammation associated with acute musculoskeletal disorders were recruited and allocated randomly to receive, orally once daily for 5-6 days, either 1.0-2.4 mg/kg robenacoxib (n=47) or 1mg/kg ketoprofen (n=21). The primary efficacy endpoint was the total clinician score, which was the sum of clinician numerical rating scale scores for pain, inflammation and mobility. Assessments were made at baseline, on day 2, and day 4 or 5. For the total clinician score, non-inferior efficacy of robenacoxib was demonstrated with a relative efficacy of 1.151 (95% confidence interval 0.872-1.494). Non-inferior efficacy of robenacoxib was also demonstrated for the secondary endpoint of the total owner score. Robenacoxib was superior (P<0.05) to ketoprofen for the owner's assessment of activity and human/animal relationship. The tolerability of both treatments was good as assessed by monitoring adverse events, clinical signs and haematology and serum biochemistry variables., (Copyright © 2012. Published by Elsevier Ltd.)

Citrullinemia is a urea cycle defect requiring long-term care with nutritional and pharmacological management. Despite treatment, morbidity and mortality of this disease remain high, and long-term complications include mild to profound mental retardation, seizures, and growth deficiency. We report a 31-year old woman with classic, neonatal-onset citrullinemia who developed progressive hypertrophic cardiomyopathy and cataracts, neither of which has been recognized previously as a complication of the disease or a consequence of long-term drug treatment., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The safety of robenacoxib, a nonsteroidal anti-inflammatory drug with high selectivity for inhibition of the cyclooxygenase (COX)-2 isoform of COX, was investigated in the cat in two randomized, blinded, placebo-controlled, parallel-group studies. Robenacoxib was administered orally to healthy young domestic short-hair cats at dosages of 0 (placebo), 5 and 10 mg/kg once daily for 28 days (study 1) and at 0 (placebo), 2, 6 and 10 mg/kg twice daily for 42 days (study 2). The recommended minimum dosage for robenacoxib tablets in cats is 1 mg/kg once daily (range 1-2.4 mg/kg). Relative to placebo treatment, no toxicologically significant effects of robenacoxib were recorded in either study, based on general observations of health, haematological and clinical chemistry variables and urinalyses in life, and by post mortem organ weight, gross pathology and histopathology assessments. Pharmacokinetic-pharmacodynamic simulations indicated that all dosages of robenacoxib were associated with marked inhibition of COX-2 at peak effect (median I(max) 97.8-99.4% inhibition) with lesser inhibition of COX-1 (median I(max) 26.8-58.3% inhibition). Inhibition of the COXs was short lasting, with >10% median inhibition persisting for 4.0 h for COX-2 and 1.5 h for COX-1. These levels of inhibition of COX-1 and COX-2 twice daily with robenacoxib were not associated with any detectable toxicity, suggesting that, as previously described in dogs, the high safety index of robenacoxib in cats may be related to a combination of its high COX-2 selectivity and short residence time in the central compartment., (© 2011 Blackwell Publishing Ltd.)

The safety of robenacoxib, a nonsteroidal anti-inflammatory drug with high selectivity for inhibition of the cyclooxygenase (COX)-2 isoform of COX, was investigated in the dog in two randomized, placebo-controlled, parallel group studies. Robenacoxib was administered orally once daily to healthy young beagle dogs at 0 (placebo), 10, 20 and 40 mg/kg for 1 month (Study 1) and at 0 (placebo), 2, 4, 6 and 10 mg/kg for 6 months (Study 2). Relative to placebo treatment, no significant adverse effects of robenacoxib were recorded in either study for clinical observations, haematological and clinical chemistry variables or macroscopic or microscopic lesions at necropsy. In Study 2, additional examinations identified no adverse effects of robenacoxib on buccal bleeding time, electrocardiographic and ophthalmoscopic examinations, urinalysis or stifle joint tissues. Pharmacokinetic-pharmacodynamic simulations indicated that all dosages of robenacoxib were associated with marked inhibition of COX-2 (median Emax 74-99% inhibition). For the highest dosage of robenacoxib (40 mg/kg in Study 1), the upper limit of the 90% tolerance interval was associated with 71% inhibition of COX-1 at Emax, but 50% inhibition persisted for only 3.5 h. This level of inhibition of COX-1 with robenacoxib was not associated with any detectable toxicity, suggesting that the high safety index of robenacoxib in dogs is a function of both its high COX-2 selectivity and short residence time in the central compartment., (© 2010 Blackwell Publishing Ltd.)

A novel mutual prodrug consisting of 4-biphenylacetic acid (BPA) and quercetin tetramethyl ether (QTME) has been synthesized as a gastrosparing NSAID, devoid of ulcerogenic side effects. The physicochemical properties, including aqueous solubility, partition coefficient, chemical stability and enzymatic hydrolysis of synthesized derivative have been studied to assess its prodrug potential. Its antiinflammatory, antiulcer and analgesic activities were also evaluated. The results indicated that BPA-QTME derivative is chemically stable, biolabile and possesses optimum lipophilicity. The synthesized compound also exhibited retention of antiinflammatory activity with reduced ulcerogenicity. Based on these observations, the therapeutic potential of this mutual prodrug is discussed., (Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.)

Purpose: We are reporting a case of bilateral corneal melt after photorefractive keratectomy requiring bilateral corneal transplantations., Results: A 35-year-old man underwent uncomplicated photorefractive keratectomy and was treated postoperatively with topical nepafenac, one drop in both eyes every 2 hours. Three days into this course of treatment, the patient developed bilateral irritation and the dose was decreased to one drop every 4 hours. The next day, he developed stromal melting in both eyes. Although nepafenac was discontinued at this point, the ulcerative keratolysis progressed in both eyes requiring penetrating keratoplasty., Conclusions: We report a case of sterile ulceration after photorefractive keratectomy surgery, which we believe was caused by frequent postoperative dosing of nepafenac.

This manuscript reports the results of preclinical studies in the rat with robenacoxib, a novel selective cyclooxygenase (COX)-2 inhibitor. Robenacoxib selectively inhibited COX-2 in vitro as evidenced from COX-1:COX-2 IC50 ratios of 27:1 in purified enzyme preparations and >967:1 in isolated cell assays. Binding to COX-1 was rapid and readily reversible (dissociation t(1/2) << 1 min), whilst COX-2 binding was slowly reversible (t(1/2) = 25 min). In vivo, robenacoxib inhibited PGE2 production (an index of COX-2 inhibition) in lipopolysaccharide (LPS)-stimulated air pouches (ID50 0.3 mg/kg) and for at least 24 h in zymosan-induced inflammatory exudate (at 2 mg/kg). Robenacoxib was COX-1 sparing, as it inhibited serum TxB2 synthesis ex vivo (an index of COX-1 inhibition) only at very high doses (100 mg/kg but not at 2-30 mg/kg). Robenacoxib inhibited carrageenan-induced paw oedema (ID50 0.40-0.48 mg/kg), LPS-induced fever (ID50 1.1 mg/kg) and Randall-Selitto pain (10 mg/kg). Robenacoxib was highly bound to plasma protein (99.9% at 50 ng/mL in vitro). After intravenous dosing, clearance was 2.4 mL/min/kg and volume of distribution at steady-state was 306 mL/kg. Robenacoxib was preferentially distributed into inflammatory exudate; the AUC for exudate was 2.9 times higher than for blood and the MRT in exudate (15.9 h) was three times longer than in blood (5.3 h). Robenacoxib produced significantly less gastric ulceration and intestinal permeability as compared with the reference nonsteroidal anti-inflammatory drug (NSAID), diclofenac, and did not inhibit PGE2 or 6-keto PGF(1alpha) concentrations in the stomach and ileum at 30 mg/kg. Robenacoxib also had no relevant effects on kidney function at 30 mg/kg. In summary, results of preclinical studies in rats studies suggest that robenacoxib has an attractive pharmacological profile for potential use in the intended target species, cats and dogs.

Purpose: Nepafenac ophthalmic suspension 0.1% was dosed topically once (QD), twice (BID), or three-times (TID) daily to assess the resolution of ocular pain and anterior-segment inflammation following cataract surgery., Methods: This was a prospective, multicenter, double-masked, randomized, placebo-controlled study of 212 adults. Patients received nepafenac 0.1% or placebo, 1 drop QD, BID, or TID beginning 1 day before cataract surgery, continuing on the day of surgery, and for 14 days thereafter. One (1) additional drop was administered 30-120 min prior to surgery. The primary efficacy endpoint was percent of treatment failures (>or=16 aqueous cells, aqueous flare = severe, or ocular pain score = moderately severe or severe) through postoperative day 14., Results: On days 7 and 14, the QD, BID, and TID all nepafenac posologies significantly reduced the percent of treatment failures, compared to placebo ( p

Objective: To investigate the efficacy, safety and the life quality improvement of uroacitides injection in the treatment for patients with advanced malignant tumors., Methods: A total of 160 patients with advanced stage cancers were enrolled into this multicenter, open and non-randomized phase II clinical trial, including cancers of the lung (33 cases), liver (45 cases), breast (17 cases), esophagus (11 cases), stomach (18 cases), colon (19 cases), pancreas (3 cases) and kidney (4 cases), and glioma (10 cases). Uroacitides was administrated in a dose of 300 ml daily via the superior vena cava catheter for consecutive 4-8 weeks., Results: Of the 160 patients, 21 dropped out and one patient died during the trial. Efficacy could be evaluated in 138 patients and safety in 160. The total objective response rate (ORR, CR + PR)) and tumor control rate (CR + PR + MR + SD) of the 138 evaluable patients were 5.8% and 65.2%, respectively. Clinical benefit response (CBR) rate was 57.2%. Major adverse effects were grade I - II and reversible nausea/vomiting (21.9%) and pain (6.3%)., Conclusion: Uroacitides injection is effective in the control for various kinds of advanced cancers with mild, reversible and tolerable adverse effects, and can also improve the patient's quality of life. It is worth being studied further.

Purpose: To assess the effects of nepafenac on corneal epithelial healing time and pain control compared to placebo in patients undergoing photorefractive keratectomy (PRK) surgery., Methods: This randomized, double-masked, placebo-controlled, single-site study included 66 adults (132 eyes) undergoing bilateral PRK surgery. Patients received 1 drop three times daily of nepafenac 0.1% in one eye and balanced salt solution in the contralateral eye until the corneal epithelium healed. Postoperatively, patients were evaluated daily for the progression of epithelial healing until complete closure was observed. Patients also were asked daily to assess the level of pain in each eye using a visual analog scale of 0 to 10., Results: There was no statistical difference between treatments in time to epithelial healing. All patients healed by postoperative day 4. Patients receiving nepafenac reported significantly less pain on postoperative days 1 (0.76 versus 1.68) and 2 (1.26 versus 2.23) compared to placebo (P<.0005). A greater percentage of patients also reported superior pain relief in the nepafenac-treated eye compared to the placebo eye during the first 3 days following surgery., Conclusions: Treatment with nepafenac 0.1% significantly reduced postoperative pain immediately following surgery and had no significant adverse effect on time to reepithelialization compared to placebo.

This report describes a patient who developed a corneal melt after the use of nepafenac, a nonsteroidal antiinflammatory drug. An 82-year-old woman with chronic cystoid macular edema after cataract extraction and intraocular lens implantation in the left eye, which was clinically controlled with a topical nonsteroidal antiinflammatory drug, was initially treated with diclofenac sodium 0.1% before being treated with nepafenac 0.1%. After 5 months of nepafenac use, the patient complained of pain, a foreign body sensation, and decreased vision in her left eye. The left eye showed a peripheral corneal ulcer with no stromal cell infiltration. The corneal ulcer was scraped and cultured to show epithelial cells and neutrophils with no growth of microorganisms. The nepafenac was discontinued, and a topical antibiotic and lubrication were used. After 2 months, the patient's visual acuity improved, and she had an intact epithelium and stable corneal thinning. To the authors' knowledge, this is the first case report of a corneal melt after the prolonged use of nepafenac to treat cystoid macular edema.

The photobiological properties of 4-acetylaminophenylacetic acid (Actarit, ACT, MS-932, CAS 18699-02-0) were studied using in vitro phototoxicity assays: photohemolysis, photoperoxidation of linoleic acid and Candida sp phototoxicity test. ACT reduced nitro blue tetrazolium (NBT) when irradiated with lambda > or = 300 nm in deoxygenated aqueous buffer solution (pH 7.4). The photohemolysis rate and photoperoxidation of linoleic acid were inhibited significantly by reduced glutathione. ACT was phototoxic to Candida sp. The isolation and identification of the photodegradation products of ACT in phosphate buffered saline solution (pH 7.4) and methanol were studied under aerobic conditions. Four compounds were identified and two of them isolated and characterized by spectroscopic methods. A photodecarboxylation with the participation of oxygen via a type I mechanism was proposed for the photodegradation of ACT which undergoes direct electron transfer from the excited state of ACT carboxylate and homolytic rupture of the alpha-carbon bond. A photodynamic mechanism involving radicals and electron transfer reactions was suggested for the observed in vitro phototoxicity.

Purpose: To compare the clinical, subjective, and objective outcomes of the use of 2 topical nonsteroidal antiinflammatory drugs--ketorolac tromethamine LS 0.4% (Acular) and nepafenac 0.1% (Nevanac)--in patients having cataract surgery., Setting: Single-center private practice, Las Vegas, Nevada, USA., Methods: One hundred eighty-three patients (193 eyes) with visually significant cataract were recruited for the study. Consenting patients were randomized to a standard regimen of Acular, gatifloxacin 0.3% (Zymar), and prednisolone acetate 1% (Pred Forte) (ketorolac group) or Nevanac, moxifloxacin hydrochloride 0.5% (Vigamox), and prednisolone acetate (Econopred) (nepafenac group). Analysis included subjective complaints (burning, itching, foreign-body sensation, pain level after surgery) and objective findings (visual function, degree of inflammation in the anterior segment, complications)., Results: The ketorolac group consisted of 94 patients (100 eyes) and the nepafenac group, 89 patients (93 eyes). The between-group differences in visual outcomes and anterior chamber inflammation were not statistically significant (mean P = .33). There was a higher incidence of posterior capsule opacification in the nepafenac group (P = 0.019). Patient satisfaction, patient compliance, and postoperative pain control were statistically significantly better in the ketorolac group (P = .022, P = .023, and P = .025, respectively)., Conclusion: Ketorolac tromethamine was statistically significantly better than nepafenac in terms of patient satisfaction, compliance, and postoperative pain control.