Pharmacology, safety, efficacy and clinical uses of the COX-2 inhibitor robenacoxib.

Robenacoxib is a veterinary-approved non-steroidal anti-inflammatory drug (NSAID) of the coxib group. It possesses anti-hyperalgesic, anti-inflammatory and anti-pyretic properties. Robenacoxib inhibits the cyclooxygenase (COX)-2 isoform of COX selectively (in vitro IC50 ratios COX-1:COX-2, 129:1 in dogs, 32:1 in cats). At registered dosages (2 mg/kg subcutaneously in dogs and cats, 1-4 mg/kg orally in dogs and 1-2.4 mg/kg orally in cats), robenacoxib produces significant inhibition of COX-2 whilst sparing COX-1. The pharmacokinetic (PK) profile of robenacoxib is characterized by a high degree of binding to plasma proteins (>98%) and moderate volume of distribution (at steady state, 240 ml/kg in dogs and 190 ml/kg in cats). In consequence, the terminal half-life in blood (<2 h) is short, despite moderate body clearance (0.81 L/kg/h) in dogs and low clearance (0.44 L/kg/h) in cats. Excretion is principally in the bile (65% in dogs and 72% in cats). Robenacoxib concentrates in inflamed tissues, and clinical efficacy is achieved with once-daily dosing, despite the short blood terminal half-life. In dogs, no relevant breed differences in robenacoxib PK have been detected. Robenacoxib has a wide safety margin; in healthy laboratory animals daily oral doses 20-fold (dog, 1 month), eight-fold (cat, 6 weeks) and five-fold (dog, 6 months) higher than recommended clinical doses were well tolerated. Clinical efficacy and safety have been demonstrated in orthopaedic and soft tissue surgery, and in musculoskeletal disorders in dogs and cats.

Antiangiogenic properties of lichen secondary metabolites.

Lichens are symbiotic organisms which are composed fungi and algae and/or cyanobacteria. They produce a variety of characteristic secondary metabolites. Such substances have various biological properties including antimicrobial, antiviral, and antitumor activities. Angiogenesis, the growth of new vessels from pre-existing vessels, contributes to numerous diseases including cancer, arthritis, atherosclerosis, infectious, and immune disorders. Antiangiogenic therapy is a promising approach for the treatment of such diseases by inhibiting the new vessel formation. Technological advances have led to the development of various antiangiogenic agents and have made possible antiangiogenic therapy in many diseases associated with angiogenesis. Some lichens and their metabolites are used in the drug industry, but many have not yet been tested for their antiangiogenic effects. The cytotoxic and angiogenic capacities of lichen-derived small molecules have been demonstrated in vivo and in vitro experiments. Therefore, some of them may be used as antiangiogenic agents in the future. The secondary compounds of lichen whose antiangiogenic effect has been studied in the literature are usnic acid, barbatolic acid, vulpinic acid, olivetoric acid, emodin, secalonic acid D, and parietin. In this article, we review the antiangiogenic effects and cellular targets of these lichen-derived metabolites.

Therapeutic Strategies for the Treatment of Chronic Hyperuricemia: An Evidence-Based Update.

This article aims to critically review the evidence on the available therapeutic strategies for the treatment of hyperuricemia. For this reason, several papers were reviewed. Xanthine oxidase inhibitors are the safest and most effective uric acid lowering drugs for the management of chronic hyperuricemia, while the efficacy of uricosuric agents is strongly modulated by pharmacogenetics. Emergent drugs (lesinurad, peglotidase) were found to be more effective for the acute management of refractory hyperuricemia, but their use is supported by a relatively small number of clinical trials so that further well-designed clinical research is needed to deepen their efficacy and safety profile.

Combined Topical Anti-inflammatory and Oral Acetazolamide in the Treatment of Central Serous Chorioretinopathy.

SIGNIFICANCE: Central serous chorioretinopathy (CSCR) is still a therapeutic challenge with no criterion standard treatment. However, anatomic changes at the level of the retinal pigment epithelium could prove of predictive value in the course of the disease for selective treatment in cases of increased risk of chronicity. PURPOSE: This pilot study analyzes the efficacy for treating acute CSCR with combined systemic acetazolamide 250 mg twice a day and nepafenac 0.1% eye drops three times a day in comparison with an untreated control group. It also evaluates the presence a pigment epithelial detachment (PED) as a risk factor for chronic CSCR. METHODS: Nineteen consecutive patients (group 1) with new or new onset of recurrent CSCR were treated with oral acetazolamide and nepafenac eye drops for at least 2 months. A control group of 14 patients (group 2) with new or new onset of recurrent CSCR were untreated while under regular observation for 4 months. Primary end points were central macular thickness and best-corrected visual acuity after 4 months. Secondary end points were complete regression of subretinal fluid at 3 months and association of PED at baseline with recurrent or chronic CSCR imaged by optical coherence tomography. RESULTS: Group 1 showed significantly faster resolution of subretinal fluid with a mean central macular thickness at 4 months of 271 ± 85 µm compared with 322 ± 79 µm for group 2 (P < .05), but with no functional benefit with a best-corrected visual acuity at 4 months of 0.8 ± 0.2 for group 1 compared with 0.9 ± 0.1 for the control group (P < .05). Patients with a small flat PED were at a higher risk of developing chronic CSCR compared with patients with a dome-shaped or no PED (P < .05). CONCLUSIONS: Central serous chorioretinopathy remains a therapeutic challenge. This pilot study shows faster resolution of subretinal fluid with treatment but without functional benefit compared with observation. The presence of small, flat PED was associated with development of chronic CSCR.

Meloxicam vs robenacoxib for postoperative pain management in dogs undergoing combined laparoscopic ovariectomy and laparoscopic-assisted gastropexy.

OBJECTIVE: To compare meloxicam and robenacoxib for short-term postoperative pain management after combined laparoscopic ovariectomy and laparoscopic-assisted gastropexy. STUDY DESIGN: Double-blind, prospective, randomised clinical trial. ANIMALS: Twenty-six client-owned female dogs. METHODS: Dogs undergoing combined laparoscopic ovariectomy and laparoscopic-assisted gastropexy were randomly divided into 2 groups. Before induction of anesthesia, 13 dogs received meloxicam (0.2 mg/kg subcutaneously), and 13 dogs received robenacoxib (2 mg/kg subcutaneously). Pain was scored with the Glasgow Composite Pain Scale (short form) before surgery and at 1, 6, 12, 18, and 24 hours after extubation. Rescue analgesia (tramadol, 3 mg/kg) was provided to dogs with a Glasgow pain score (GPS) ≥5. Glasgow pain scores were analyzed by ANOVA with treatment, age, and surgical time as fixed factors. RESULTS: Glasgow pain scores were higher at 24 hours postsurgery in dogs treated with robenacoxib (2.18 ± 0.29) compared with those treated with meloxicam (0.68 ± 0.41, P = .04). Two dogs treated with meloxicam and 7 dogs treated with robenacoxib required rescue analgesia. Regardless of the treatment, the overall GPS was lower at 18 and 24 hours postsurgery when the surgical time was >40 minutes compared with surgical times ≤40 minutes, but surgical site inflammation was likely a confounding factor in this finding. Glasgow pain score was not affected by patient age. CONCLUSION: Meloxicam was more effective than robenacoxib at controlling pain in the population of dogs reported here. CLINICAL SIGNIFICANCE: Preoperative administration of meloxicam effectively controls pain for 24 hours after combined laparoscopic ovariectomy and laparoscopic-assisted gastropexy, but rescue analgesia may be required.

New urate-lowing therapies.

PURPOSE OF REVIEW: To discuss recent studies of lesinurad and arhalofenate. RECENT FINDINGS: Lesinurad acts by blocking urate reabsorption channels URAT-1 and OAT-4. It has urate-lowering effect when used alone and in combination with xanthine oxidase inhibitors (XOIs). Its uricosuric activity depends on glomerular filtration, and its' efficacy is impaired at eGFR less than 30 ml/min. Lesinurad monotherapy (400 mg/day) associates with serum creatinine elevations. However, this risk is substantially attenuated with coprescription of a XOI and when prescribed at a dose of 200 mg/day. Given its' modest urate-lowering effect, and the risk of serum creatinine elevation when used alone, it is licenced for use in combination with XOI for people unable to achieve target serum uric acid with XOI alone. Lesinurad does not have the drug interactions associated with probenecid, however, it is metabolized by CYP2C9, and should be used with caution if CYP2C9 inhibitors are coprescribed. Arhalofenate also acts by blocking URAT-1; however, it also blocks the NALP-3 inflammasome providing gout-specific anti-inflammatory effect. Arhalofenate has a weaker urate-lowering effect than lesinurad and further phase III evaluation is planned. SUMMARY: Lesinurad provides an additional option for people with gout unable to achieve target serum uric acid with XOI alone.

Prenatal treatment of ornithine transcarbamylase deficiency.

PURPOSE OF STUDY: Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor. METHODS USED: Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery. SUMMARY OF RESULTS: Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years. CONCLUSION: Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

[Visual disorder after visual contact with a geodetic laser]. / Visual disorder after visual contact with a geodetic laser.

Macular edema is a rare complication that can occur under the influence of light. Damage occurs as a result of focusing the light beam on the macula. A 23-year-old patient reported to the hospital due to a sudden reduction in visual acuity of the left eye after visual contact with a geodetic laser at work. After full diagnosis and treatment implementation after 3 weeks, vision improvement was achieved. The case report shows the harmful effects of laser techniques on human vision.

Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor.

UNLABELLED: Learning and memory impairments are common in traumatic brain injury (TBI) survivors. However, there are no effective treatments to improve TBI-induced learning and memory impairments. TBI results in decreased cAMP signaling and reduced cAMP-response-element binding protein (CREB) activation, a critical pathway involved in learning and memory. TBI also acutely upregulates phosphodiesterase 4B2 (PDE4B2), which terminates cAMP signaling by hydrolyzing cAMP. We hypothesized that a subtype-selective PDE4B inhibitor could reverse the learning deficits induced by TBI. To test this hypothesis, adult male Sprague-Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. At 3 months postsurgery, animals were administered a selective PDE4B inhibitor or vehicle before cue and contextual fear conditioning, water maze training and a spatial working memory task. Treatment with the PDE4B inhibitor significantly reversed the TBI-induced deficits in cue and contextual fear conditioning and water maze retention. To further understand the underlying mechanisms of these memory impairments, we examined hippocampal long-term potentiation (LTP). TBI resulted in a significant reduction in basal synaptic transmission and impaired expression of LTP. Treatment with the PDE4B inhibitor significantly reduced the deficits in basal synaptic transmission and rescued LTP expression. The PDE4B inhibitor reduced tumor necrosis factor-α levels and increased phosphorylated CREB levels after TBI, suggesting that this drug inhibited molecular pathways in the brain known to be regulated by PDE4B. These results suggest that a subtype-selective PDE4B inhibitor is a potential therapeutic to reverse chronic learning and memory dysfunction and deficits in hippocampal synaptic plasticity following TBI. SIGNIFICANCE STATEMENT: Currently, there are an estimated 3.2-5.3 million individuals living with disabilities from traumatic brain injury (TBI) in the United States, and 8 of 10 of these individuals report cognitive disabilities (Thurman et al., 1999; Lew et al., 2006; Zaloshnja et al., 2008). One of the molecular mechanisms associated with chronic cognitive disabilities is impaired cAMP signaling in the hippocampus. In this study, we report that a selective phosphodiesterase 4B (PDE4B) inhibitor reduces chronic cognitive deficits after TBI and rescues deficits in hippocampal long-term potentiation. These results suggest that PDE4B inhibition has the potential to improve learning and memory ability and overall functioning for people living with TBI.

NR4A1-dependent Ly6Clow monocytes contribute to reducing joint inflammation in arthritic mice through Treg cells.

Monocytes are central to the physiopathology of arthritis, but their roles in progression and resolution of the disease remain to be clarified. Using NR4A1-/- mice, which lack patrolling lymphocyte antigen 6C (Ly6Clow ) monocytes, we found that inflammatory Ly6Chigh monocytes contribute to rapid development of arthritis in a serum transfer-induced arthritis (STIA) model. Our experiments suggest that patrolling monocytes do not promote the initiation and progression of arthritis in mice, as severity of symptoms was amplified in NR4A1-/- mice. Moreover, we show that treatment of arthritic wild type (WT) mice with cytosporone B (Csn-B), a NR4A1-specific agonist, significantly reduces severity of disease. Effects of Csn-B were absent in monocyte-depleted mice treated with clodronate until Ly6Clow monocytes were restored. Adoptive transfer of Ly6Clow monocytes in arthritic NR4A1-/- mice treated with Csn-B reduces joint inflammation, supporting the regulatory role of Ly6Clow subset on disease development. Our results also reveal that administration of Csn-B to arthritic mice enhances levels of circulating CD4+ CD25+ FoxP3+ Treg cells, a process requiring the presence of Ly6Clow monocytes. Together, these data indicate that Ly6Chigh monocytes are involved in the initiation and progression of arthritis and Ly6Clow monocytes contribute to reduce joint inflammation through the mobilization of Treg cells.

Brain MRS glutamine as a biomarker to guide therapy of hyperammonemic coma.

Acute idiopathic hyperammonemia in an adult patient is a life-threatening condition often resulting in a rapid progression to irreversible cerebral edema and death. While ammonia-scavenging therapies lower blood ammonia levels, in comparison, clearance of waste nitrogen from the brain may be delayed. Therefore, we used magnetic resonance spectroscopy (MRS) to monitor cerebral glutamine levels, the major reservoir of ammonia, in a gastric bypass patient with hyperammonemic coma undergoing therapy with N-carbamoyl glutamate and the ammonia-scavenging agents, sodium phenylacetate and sodium benzoate. Improvement in mental status mirrored brain glutamine levels, as coma persisted for 48h after plasma ammonia normalized. We hypothesize that the slower clearance for brain glutamine levels accounts for the delay in improvement following initiation of treatment in cases of chronic hyperammonemia. We propose MRS to monitor brain glutamine as a noninvasive approach to be utilized for diagnostic and therapeutic monitoring purposes in adult patients presenting with idiopathic hyperammonemia.

Efficacy and safety of oral robenacoxib (tablet) for the treatment of pain associated with soft tissue surgery in client-owned dogs.

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.

Evaluation of the dose-response relationship of oral robenacoxib in urate crystal-induced acute stifle synovitis in dogs.

The objective of the study was to establish the dose-response relationship for robenacoxib, a selective cyclooxygenase (COX)-2 inhibitor, in a urate crystal model of acute synovitis. In a randomized partial Latin square design trial, 12 beagle dogs were administered orally single doses of robenacoxib (0.5, 1, 2, 4 and 8 mg/kg), placebo and the positive control meloxicam (0.1 mg/kg), 3 h after injection of sodium urate crystals into a stifle joint. Dogs were assessed for weight bearing on a force plate and by subjective clinical orthopaedic observations. Robenacoxib produced dose-dependent improvement in weight bearing, and decreased pain on palpation and joint swelling, over the dose range 0.5-2 mg/kg with no further increase in effect over the range 2-8 mg/kg. For weight bearing on the force plate, the ED50 of robenacoxib was 0.6-0.8 mg/kg. The onset of action and time to peak effect of robenacoxib were faster (respectively, 2-2.5 h and 3-5 h) than for meloxicam (respectively, 3 h and 6 h). Robenacoxib significantly inhibited COX-2 at all doses, with dose-related activity. Robenacoxib did not inhibit COX-1 over the dose range 0.5-4 mg/kg, but produced transient inhibition at 8 mg/kg. In conclusion, oral administration of robenacoxib over the dose range 0.5-8 mg/kg demonstrated significant analgesic and anti-inflammatory efficacy in dogs.

DF2755A, a novel non-competitive allosteric inhibitor of CXCR1/2, reduces inflammatory and post-operative pain.

The activation of CXCR1/2 has been implicated in the genesis of inflammatory and postoperative pain. Here, we investigated a novel orally acting allosteric inhibitor of CXCR1/2 (DF2755A) and evaluated its antinociceptive effect in several models of inflammatory and post-operatory pain. DF2755A was tested in vitro for efficacy in the chemotaxis assay, selectivity and toxicity. In vivo, C57Bl/6 mice were treated orally with DF2755A and the following experiments were performed: pharmacokinetic profile; inflammatory hyperalgesia models using electronic pressure meter test; neutrophil migration assay assessed by myeloperoxidase assay. DF2755A selectively inhibited neutrophil chemotaxis induced by CXCR1/2 ligands without effect on CXCL8 binding to neutrophils. A single mutation of the allosteric site at CXCR1 abrogated the inhibitory effect of DF2755A on CXCL8-induced chemotaxis. DF2755A given orally was well absorbed (88.2%), and it was able to reduce, in a dose (3-30mg/kg)-dependent manner, inflammatory hyperalgesia induced by carrageenan, LPS and CXCL1/KC as well as neutrophil recruitment and IL-1ß production. In addition, DF2755A was able to reduce post-incisional nociception. Therapeutic treatment with DF2755A reduced CFA-induced inflammatory hyperalgesia even when injected intrathecally. The present results indicate that DF2755A is a novel selective allosteric inhibitor of CXCR1/2 with a favorable oral pharmacokinetic profile. Furthermore, the results might suggest that DF2755A might be a candidate of a novel therapeutic option to control inflammatory and post-operative pain.

Cystoid macular edema associated with iridocorneal endothelial syndrome: a case report.

BACKGROUND: Iridocorneal endothelial (ICE) syndrome occurs mainly in young and middle-aged women and typically presents as a unilateral disease characterized by abnormalities of the iris and corneal endothelium. While the ICE syndrome is known to be associated with glaucoma and bullous keratopathy, to our knowledge, only two cases of ICE syndrome complicated with cystoid macular edema (CME) have been reported to date. In this paper, we report a case of ICE syndrome complicated with CME treated at our institution. CASE PRESENTATION: The subject was a 51-year-old woman. In October 2013, she was examined by a primary care physician for blurred vision in her left eye. Dyscoria and abnormality of the corneal endothelium were observed, and the patient was diagnosed with ICE syndrome. In November of the same year, she was referred to our institution with a decrease in visual acuity and CME, both in her left eye. At initial examination, her best corrected decimal visual acuity was 1.0 (Snellen equivalent: 20/20) in the right eye and 0.5 (20/40) in the left eye. Intraocular pressure was 12 mmHg in both eyes. She was diagnosed with Cogan-Reese syndrome based on marked ectropion uveae, peripheral anterior synechia, and abnormalities of the corneal endothelium. Marked CME was observed on ophthalmoscopy and optical coherence tomography. A topical non-steroidal anti-inflammatory drug (nepafenac 0.1 %) was applied to the left eye four times daily from January 2014. Four weeks later, the CME had resolved and her visual acuity was 1.0 (20/20). CONCLUSION: While non-steroidal anti-inflammatory drugs and steroids did not appear to be effective in two previously reported cases of ICE syndrome complicated with CME, topical nepafenac was effective in this case. However, more such cases are needed before concluding that topical nepafenac is effective in this situation.

The opinion of the Expert Group of the Polish Society of Ophthalmology on using nepafenac in the prevention of postoperative macular edema after cataract surgery in diabetic patients.

Nepafenac is an innovative non-steroidal anti-inflammatory drug used in ophthalmology for the prevention of macular edema after cataract surgery. Along with its anti-inflammatory effect, nepafenac has some unique properties which distinguish it from other non-steroidal anti-inflammatory drugs. It is a prodrug activated to amfenac after it penetrates through the corneal layers to the aqueous humour and the ciliary body. Having electrically neutral molecules of lipophilic properties, nepafenac does not accumulate in the cornea and does not cause its degeneration. Additionally, it quickly achieves higher concentrations in the aqueous humour as compared to other non-steroidal anti-inflammatory drugs. Nepafenac shows high selectivity and activity against COX-2 isoform, the key enzyme implicated in inducing inflammation, which is the main cause of macular edema. Furthermore, nepafenac has the unique scleral and suprachoroidal distribution pathways. Finally, its effect on the intraocular pressure is none to negligible. Nepafenac treatment should be initiated prior to cataract surgery and continued long enough to reduce the risk of late-onset macular edema. The Expert Group of the Polish Society of Ophthalmology consider using nepafenac in the prevention of post­operative macular edema in diabetic patients undergoing cataract surgery as expedient and reasonable. The proposed optimum pre- and postoperative treatment regimen can be modified for individualised therapy.

New medications in development for the treatment of hyperuricemia of gout.

PURPOSE OF REVIEW: To update recent developments in medications targeting hyperuricemia, but not including medications recently labelled in the European Union and the United States. RECENT FINDINGS: A new xanthine oxidase inhibitor, Topiloric (Fujiyakuhin Co., Ltd. Japan) Uriadec (Sanwa Kagaku Kenkyusho Co., Ltd. Japan), has been developed and labelled in Japan. An inhibitor of purine nucleoside phosphorylase, Ulodesine, is in development in combination with allopurinol. The rest of the medications in the pipeline for hyperuricemia are targeting renal transporters of uric acid, mainly URAT1 and OAT4, acting as uricosuric agents. Most of them, such as lesinurad and arhalofenate, are being tested in trials in combination with allopurinol and febuxostat. The most potent RDEA3170 is being tested in monotherapy, but also associated with febuxostat. Recently, medications showing dual activity, inhibiting both xanthine oxidoreductase and URAT1, have been communicated or started exploratory clinical trials. There is no report of medications targeting other transporters such as Glut9 or ABCG2. SUMMARY: There are a number of medications in the pipeline targeting hyperuricemia, mostly uricosurics in combination with xanthine oxidase inhibitors, but some targeting both xanthine oxidoreductase and URAT1. Increasing the number of available medications will ensure proper control of hyperuricemia to target serum urate levels in the near future for most, if not all, patients with hyperuricemia.

Activation of mGluR5 Attenuates Microglial Activation and Neuronal Apoptosis in Early Brain Injury After Experimental Subarachnoid Hemorrhage in Rats.

Activation of metabotropic glutamate receptor 5 (mGluR5) provided neuroprotection in multiple central nervous system injury, but the roles of mGluR5 in subarachnoid hemorrhage (SAH) remain unclear. In present study, we aimed to evaluate whether activation of mGluR5 attenuates early brain injury (EBI) after experimental SAH in rats. We found that selective mGluR5 orthosteric agonist CHPG or positive allosteric modulator VU0360172 administration significantly improves neurological function and attenuates brain edema at 24 h after SAH. Furthermore, mGluR5 obviously expresses in activated microglia (ED-1 positive) after SAH. CHPG or VU0360172 administration significantly reduces the numbers of activated microglia and the protein and mRNA levels of pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α at 24 h after SAH. Moreover, CHPG or VU0360172 administration obviously reduces the number of TUNEL-positive cells and active caspase-3/NeuN-positive neurons in cortex at 24 h after SAH. CHPG or VU0360172 administration significantly up-regulates the expression of Bcl-2, and down-regulates the expression of Bax and active caspase-3, which in turn increases the ratio of Bcl-2/Bax. Our results indicate that activation of mGluR5 attenuates microglial activation and neuronal apoptosis, and improves neurological function in EBI after SAH.

Biological effects and clinical efficacy of a topical Toll-like receptor 7 agonist in seasonal allergic rhinitis: a parallel group controlled phase IIa study.

OBJECTIVE AND DESIGN: The purpose of the study was to examine effects of pre-treatment with a Toll-like receptor 7 (TLR7) agonist (AZD8848) in allergic rhinitis and to evaluate clinical effects of two dosing regimens. SUBJECTS: The study involved 83 patients with allergic rhinitis. Data on effects of AZD8848 on symptoms were analysed with data from a previous study (n = 68) of identical double blind, parallel group design (NCT00770003). TREATMENT: The treatment involved intranasal AZD8848 20 µg three times weekly, 60 µg once weekly, or placebo for 5 weeks. METHODS: Nasal lavage and plasma were analysed for proof-of-mechanism markers. Daily nasal allergen challenges were given for 7 days, starting 24 h after the final AZD8848 dose. Symptoms were monitored after each challenge and every morning and evening. RESULTS: Markers of TLR-activation increased following AZD8848 administration (CXCL10, TNFα, IL-6, IFNγ). Symptoms recorded soon after allergen challenge were reduced up to eight days after the final dose of AZD8848. Morning and evening symptoms were also reduced, and these changes reached statistical significance for morning observations. Adverse effects were more frequent in the 20 µg three times weekly group. CONCLUSIONS: Repeated administration of AZD8848 activated TLR7 and produced IFN-induced effects. This was associated with a sustained reduction in allergen responsiveness.

Topical Nonsteroidal Anti-Inflammatory Drugs: The Importance of Drug, Delivery, and Therapeutic Outcome.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain associated with a variety of indications, including arthritic conditions, but their usefulness is often limited by dose-dependent adverse events (AEs), such as gastrointestinal disturbances, cardiovascular events, and renal toxicity. The risk of such effects could be reduced by the use of topical formulations, which offer the potential to deliver analgesic concentrations locally, at the site of inflammation, while minimizing systemic concentrations. The topical preparations currently approved in the United States are diclofenac sodium 1.5% topical solution (containing dimethyl sulfoxide as a penetration enhancer), diclofenac sodium gel 1%, and a diclofenac hydroxyethylpyrrolidine 1.3% patch. Each of these topical NSAIDs provide drug delivery to subcutaneous tissues for the management of pain associated with osteoarthritis or soft-tissue injuries. Furthermore, these formulations are not significantly associated with the systemic AEs associated with oral NSAIDs; the most common AEs associated with topical formulations are local skin reactions, which are usually mild and self-limiting. Other topical NSAID preparations approved in the European Union include ibuprofen creams and gels, ketoprofen gel, felbinac gel and cutaneous foam, and piroxicam gel. Meta-analyses have confirmed the efficacy and safety of these preparations. However, it is important to recognize that pharmacokinetic absorption from topical formulations can vary markedly, even between different formulations of the same drug, depending on the agent, the underlying disorder, and the site of application. It is therefore essential to consider the patient, the drug, and the drug delivery mechanism when selecting a topical NSAID preparation.