Comparison of postcataract surgery anti-inflammatory regimens on the incidence of cystoid macular edema, iritis, pain, and photophobia.

PURPOSE: To compare postcataract surgery anti-inflammatory regimens of intracanalicular dexamethasone insert and topical bromfenac on the incidence of cystoid macular edema (CME), iritis, pain, and photophobia. SETTING: Eyes of York Cataract & Laser Center, York, Pennsylvania. DESIGN: Retrospective chart review. METHODS: Case records of 647 consecutive patients (1001 eyes) who underwent cataract surgery and received dexamethasone intracanalicular insert 0.4 mg (Group 1; 482 eyes) or topical nonsteroidal anti-inflammatory drug (NSAID) (bromfenac 0.075% 2 times a day) for 4 weeks postoperatively (Group 2; 519 eyes) were included. Both groups received intracameral moxifloxacin and phenylephrine/ketorolac. Patients with prior CME, vitreomacular traction, combined cataract/glaucoma surgery, and medication protocols different from those examined in this study were excluded. RESULTS: Compared with the dexamethasone insert group, the topical NSAID group had a significantly lower incidence of CME (0.4% [2/519] vs 3.9% [19/482], P < .001) and photophobia (1.9% [10/519] vs 4.8% [23/482], P = .012). The incidence of breakthrough iritis (3.5% [18/519] vs 5.6% [27/482], P = .104) and pain also trended lower (4.0% [21/519] vs 5.4% [26/482], P = .314) in the topical NSAID group. CONCLUSIONS: Topical NSAIDs were found to be more effective in controlling CME, pain, iritis, and photophobia after cataract surgery compared with the intracanalicular dexamethasone insert in the presence of intracameral phenylephrine/ketorolac.

Matching-adjusted indirect comparison of phase 3 clinical trial outcomes: OC-01 (varenicline solution) nasal spray and cyclosporine a 0.05% ophthalmic emulsion for the treatment of dry eye disease.

BACKGROUND: Matching-adjusted indirect comparison (MAIC) is a validated and widely accepted statistical method that derives indirect comparisons between treatments when head-to-head studies have not been performed. OBJECTIVE: To compare the efficacy of OC-01 varenicline nasal spray (OC-01 VNS) 0.03 mg to cyclosporine A (CsA) 0.05% ophthalmic emulsion on tear production in patients with dry eye disease based on data from the respective phase 3 clinical trials using the MAIC technique. METHODS: Individual patient data were drawn from the phase 3 registry trial of OC-01 VNS; aggregate data were drawn from 2 phase 3 trials of CsA in the publicly available New Drug Application for CsA 0.05% ophthalmic emulsion (RESTASIS). Using unanchored MAIC methods, the individual patient data were weighted based on 4 clinically relevant baseline variables (age, race, sex, and baseline Schirmer test score [STS]) to produce a weighted OC-01 VNS dataset matched to the key demographics of the CsA dataset. Least-squares mean change from baseline in STS for OC-01 VNS was calculated using the identical analysis of variance model used to calculate the same value for CsA in the RESTASIS New Drug Application, which were then compared. Proportions of subjects with improvement of 10 mm or more from baseline in STS were compared in the weighted OC-01 VNS and CsA dataset. Time points available for comparisons were CsA trials at 3 and 6 months and OC-01 data at 2 and 4 weeks. RESULTS: Data from 511 subjects in the OC-01 VNS phase 3 trial and 585 in the CsA phase 3 trials were analyzed. The least-squares mean STS change from baseline for OC-01 VNS at 2 and 4 weeks was significantly higher than that for CsA at 3 and 6 months (P < 0.0001 for all comparisons). Mean STS improvements were approximately 6-7 mm for OC-01 VNS and approximately 1 mm for CsA. The proportion of subjects with improvement of 10 mm or more from baseline in STS was significantly higher for OC-01 VNS (50.2%) than CsA (11.7 and 17.1% in the 2 CsA studies; P < 0.0001 for both comparisons). CONCLUSIONS: This MAIC analysis demonstrates OC-01 VNS produces significantly greater improvement in mean STS and results in significantly greater numbers of patients with substantial improvement in STS (percentage ≥ 10 mm) compared with CsA. Together, absent more robust data from head-to-head trials, findings may suggest a potentially greater magnitude of improvement achieved with OC-01 VNS compared with CsA for the treatment of dry eye disease within conditions of the analysis methodology. DISCLOSURES: Dr Visco was a consultant for Novartis, Allergan, and Oyster Point, Inc. Ms Hendrix and Drs Macsai and Gibson are employees and shareholders for Oyster Point Pharma, Inc. Drs Sun and Tam participated in clinical research and received funding from Oyster Point Pharma, Inc. Oyster Point Pharma, Inc sponsored the Phase 3 OC-01 (varenicine solution) clinical study from which analysis data are obtained.

Effect of intracameral phenylephrine 1.0%-ketorolac 0.3% on postoperative cystoid macular edema, iritis, pain, and photophobia after cataract surgery.

PURPOSE: To assess the effectiveness of intracameral phenylephrine-ketorolac during cataract surgery compared with postoperative topical steroids in reducing the incidence of postoperative clinical cystoid macular edema (CME) confirmed via optical coherence tomography (OCT), breakthrough iritis, pain, and photophobia. SETTING: Ambulatory surgical center/clinical practice. DESIGN: Retrospective 2-cohort study. METHODS: This study of cataract surgery patients compared the incidence of postoperative CME, breakthrough iritis, pain, and photophobia between patients receiving either intracameral phenylephrine 1.0%-ketorolac 0.3% during surgery or topical loteprednol 0.5% 2 days preoperatively, tapered postoperatively. Patients with prior CME or at high risk for postoperative CME, combined cataract/glaucoma surgery, and medication protocols different from those studied here were excluded. All eyes received bromfenac 2 days preoperatively and 10 weeks postoperatively. RESULTS: The study enrolled 2218 eyes (n = 1402). The phenylephrine/ketorolac treatment group included 1334 eyes (n = 830) and the topical loteprednol control group included 884 eyes (n = 572). The groups were comparable in age, race, gender, and perioperative characteristics. Clinical CME incidence was significantly lower in the phenylephrine-ketorolac group (0.52% vs 1.47%, P = .021). The phenylephrine-ketorolac group also had significantly lower breakthrough iritis (1.72% vs 4.86%, P < .001) and pain (1.27% vs 4.19%, P < .001) than the topical loteprednol group. The incidence of photophobia trended lower for the phenylephrine/ketorolac group relative to the topical loteprednol group (0.90% vs 1.13%, respectively, P = .590) but was not statistically significant. CONCLUSIONS: Intracameral phenylephrine/ketorolac and topical nonsteroidal antiinflammatory drugs (NSAIDs) without postoperative topical steroids significantly reduced postoperative clinical CME, breakthrough iritis, and pain after cataract surgery when compared with conventional perioperative topical steroids and NSAIDs.

Femtosecond laser-assisted arcuate keratotomy at the time of cataract surgery for the management of preexisting astigmatism.

PURPOSE: To evaluate the outcomes of femtosecond laser-assisted arcuate keratotomy combined with cataract surgery in eyes with low-to-moderate corneal astigmatism. SETTING: Eyes of York Private Practice Ophthalmology Clinic, York, Pennsylvania, USA. DESIGN: Retrospective case series. METHODS: This retrospective analysis included case records of patients with preexisting corneal astigmatism ranging from 0.5 to 2.0 diopter (D). Study parameters included corneal astigmatism, refractive astigmatism, and uncorrected (UDVA) and corrected (CDVA) distance visual acuities. The results, which were analyzed at 3 months postoperatively, included frequency distribution histograms, vector analysis, and single-angle polar plots. RESULTS: The study comprised case records of 189 eyes of 143 patients (56 men and 87 women). The postoperative refractive astigmatism was reduced significantly compared with preoperative corneal astigmatism to 0.14 D ± 0.23 (SD) from 0.92 ± 0.34 D (P < .001). One hundred eighty-one eyes (95.8%) demonstrated postoperative refractive astigmatism of 0.5 D or less. The mean surgically induced change along the preoperative steep axis was -0.59 ± 0.56 D, and the change along the orthogonal axis was 0.01 ± 0.35 D. Postoperatively, 171 eyes (90.5%) had astigmatism angle of error of 15 degrees or less. The postoperative mean UDVA and CDVA were 0.09 ± 0.16 logarithm of the minimum angle of resolution (logMAR) and 0.02 ± 0.05 logMAR, respectively. One hundred seventy eyes (90%) had a postoperative UDVA of 20/30 or better. The results demonstrated stability at 12 months postoperatively. No intraoperative or postoperative arcuate keratotomy-related events were observed. CONCLUSION: The results suggest that femtosecond laser-assisted arcuate keratotomy represents a safe and effective method for astigmatism correction at the time of cataract surgery with demonstrated stability of correction for at least 1 year postoperatively.

Effect of phenylephrine/ketorolac on iris fixation ring use and surgical times in patients at risk of intraoperative miosis.

PURPOSE: To evaluate the effect of intracameral phenylephrine/ketorolac (1%/0.3%) during cataract surgery on the use of iris fixation ring and surgical time in patients with poor pupil dilation (≤5.0 mm) or intraoperative floppy iris syndrome (IFIS). SETTING: Private practice outpatient surgical center. DESIGN: This retrospective analysis was conducted from January 1, 2014 to October 7, 2015. MATERIALS AND METHODS: The use of iris fixation rings was evaluated in a retrospective analysis of 46 patients who underwent cataract surgery from January 1, 2014, to October 7, 2015, and who were identified before surgery to be at risk for intraoperative miosis. The qualifying factors were presurgical examination of pupil dilation ≤5.0 mm after being administered topical tropicamide 1% and phenylephrine 2.5% or history of IFIS during surgery in the fellow eye. All patients received a 2-day preoperative course of topical nonsteroidal anti-inflammatory drugs (NSAIDs) and day-of-surgery preoperative dilation using topical cyclopentolate 1%, tropicamide 1%, and phenylephrine 10%. Phenylephrine/ketorolac 1%/0.3% (Omidria®) or epinephrine 1:1,000 with sulfites was added to the ophthalmic irrigation solution and delivered intracamerally at the start of the procedure and throughout surgery. The use of iris fixation rings and surgical time for each patient were captured for each group. RESULTS: Eighteen (50%) of the patients in the epinephrine group and no patients in the phenylephrine/ketorolac group required iris fixation ring insertion to maintain pupil dilation or to control IFIS (p=0.0034). Mean surgical time was significantly shorter in the group of patients who received phenylephrine/ketorolac (p=0.0068). CONCLUSION: In this retrospective cohort analysis of patients with poorly dilated pupils and/or IFIS, the use of intracameral phenylephrine/ketorolac in patients at risk for intraoperative miosis resulted in significantly less iris fixation ring use and significantly shorter surgical time when compared with intracameral epinephrine use.

Discovery of N-[Bis(4-methoxyphenyl)methyl]-4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxamide (MK-8617), an Orally Active Pan-Inhibitor of Hypoxia-Inducible Factor Prolyl Hydroxylase 1-3 (HIF PHD1-3) for the Treatment of Anemia.

The discovery of novel 4-hydroxy-2-(heterocyclic)pyrimidine-5-carboxamide inhibitors of hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD) is described. These are potent, selective, orally bioavailable across several species, and active in stimulating erythropoiesis. Mouse and rat studies showed hematological changes with elevations of plasma EPO and circulating reticulocytes following single oral dose administration, while 4-week q.d. po administration in rat elevated hemoglobin levels. A major focus of the optimization process was to decrease the long half-life observed in higher species with early compounds. These efforts led to the identification of 28 (MK-8617), which has advanced to human clinical trials for anemia.

Optimization of erythropoietin production with controlled glycosylation-PEGylated erythropoietin produced in glycoengineered Pichia pastoris.

Pichia pastoris is a methylotropic yeast that has gained great importance as an organism for protein expression in recent years. Here, we report the expression of recombinant human erythropoietin (rhEPO) in glycoengineered P. pastoris. We show that glycosylation fidelity is maintained in fermentation volumes spanning six orders of magnitude and that the protein can be purified to high homogeneity. In order to increase the half-life of rhEPO, the purified protein was coupled to polyethylene glycol (PEG) and then compared to the currently marketed erythropoiesis stimulating agent, Aranesp(®) (darbepoetin). In in vitro cell proliferation assays the PEGylated protein was slightly, and the non-PEGylated protein was significantly more active than comparator. Pharmacodynamics as well as pharmacokinetic activity of PEGylated rhEPO in animals was comparable to that of Aranesp(®). Taken together, our results show that glycoengineered P. pastoris is a suitable production host for rhEPO, yielding an active biologic that is comparable to those produced in current mammalian host systems.

Discovery of betamethasone 17alpha-carbamates as dissociated glucocorticoid receptor modulators in the rat.

A series of betamethasone 17alpha-carbamates were designed, synthesized, and evaluated for their ability to dissociate the two main functions of the glucocorticoid receptor, that is, transactivation and transrepression, in rat cell lines. A number of alkyl substituted betamethasone 17alpha-carbamates were identified with excellent affinity for the glucocorticoid receptor (e.g., 7, GR IC(50) 5.1 nM) and indicated dissociated profiles in functional assays of transactivation (rat tyrosine aminotransferase, TAT, and rat glutamine synthetase, GS) and transrepression (human A549 cells, MMP-1 assay). Gratifyingly, the in-vivo profile of these compounds, for example, 7, also indicated potent anti-inflammatory activity with impaired effects on glucose, insulin, triglycerides, and body weight. Taken together, these results indicate that dissociated glucocorticoid receptor modulators can be identified in rodents.

Chemical genetics define the roles of p38alpha and p38beta in acute and chronic inflammation.

The p38 MAP kinase signal transduction pathway is an important regulator of proinflammatory cytokine production and inflammation. Defining the roles of the various p38 family members, specifically p38alpha and p38beta, in these processes has been difficult. Here we use a chemical genetics approach using knock-in mice in which either p38alpha or p38beta kinase has been rendered resistant to the effects of specific inhibitors along with p38beta knock-out mice to dissect the biological function of these specific kinase isoforms. Mice harboring a T106M mutation in p38alpha are resistant to pharmacological inhibition of LPS-induced TNF production and collagen antibody-induced arthritis, indicating that p38beta activity is not required for acute or chronic inflammatory responses. LPS-induced TNF production, however, is still completely sensitive to p38 inhibitors in mice with a T106M point mutation in p38beta. Similarly, p38beta knock-out mice respond normally to inflammatory stimuli. These results demonstrate conclusively that specific inhibition of the p38alpha isoform is necessary and sufficient for anti-inflammatory efficacy in vivo.

Antiarthritic effects of relaxin, in combination with estrogen, in rat adjuvant-induced arthritis.

The incidence and severity of rheumatoid arthritis (RA) are reduced during pregnancy. Estradiol-17beta and relaxin (RLX), hormones of pregnancy, are implicated in decreased immune responsiveness. The aim of this study was to determine the effects of estrogen and RLX, alone or in combination, on the development of adjuvant-induced arthritis (AIA) in ovariectomized (OVX) Lewis rats. Arthritis was induced on day 0 by adjuvant injection in the left hind paw. Rats were treated with estradiol valerate (E), porcine RLX, E + RLX, or vehicle. Healthy OVX control animals were used for comparison. Treatment with RLX or E alone decreased adjuvant-induced inflammation in both the injected (primary) and noninjected (secondary) hind paws. Combined treatment with E and RLX was more effective than either hormone alone in blocking secondary paw inflammation. Furthermore, E plus RLX reduced changes to spleen and thymus weights induced by adjuvant injection. Both E and RLX alone decreased circulating tumor necrosis factor (TNF) alpha. The combination of E and RLX resulted in a greater decline in TNFalpha than treatment with either hormone alone. There was no effect of hormones on the proinflammatory cytokine, interleukin (IL)-1beta. The anti-inflammatory cytokine IL-10 increased in response to E and E plus RLX. In conclusion, combined therapy with E and RLX was more effective than either hormone alone in reducing chronic inflammation, joint changes, and high circulating TNFalpha associated with AIA in rats. Accordingly, these hormones could play a role in reducing RA-induced inflammation during pregnancy by an effect on the immune system.

p38 MAP kinase inhibitors. Part 5: discovery of an orally bio-available and highly efficacious compound based on the 7-amino-naphthyridone scaffold.

A new sub-class of p38 inhibitors represented by 7-amino-naphthyridone have been discovered. Benchmark compound 16 potently inhibited p38 in vitro, was functionally active, and displayed excellent pharmacokinetic profiles in two animal species. Compound 16 reduced inflammation in animal disease models at EC(50) doses as low as 0.2mpk.

Evaluation of a potential stress effect in rat adjuvant arthritis by using a new and efficient plethysmograph.

We describe the basis of a new design for a user-friendly and easily reproduced mercury-displacement plethysmograph. This system was validated using the rat adjuvant-induced arthritis model in female Lewis rats. Furthermore, 2 different caging systems were evaluated to ensure that caging did not have an effect on disease progression and severity. These groups were evaluated further under frequent- and infrequent-handling conditions. Housing had less effect on the amount of swelling seen during the disease than did the amount of handling. Frequent handling significantly reduced the degree of paw swelling. Frequently handled, arthritic rats housed 5 rats per cage in the Box B system also lost a biologically significant amount of weight by the end of the study. Therefore, we do not recommend housing more than 4 rats per cage under these conditions.

Effects of relaxin in a model of rat adjuvant-induced arthritis.

A reduction in the incidence and severity of rheumatoid arthritis is seen in pregnant women. Relaxin, a hormone of pregnancy, has been implicated in decreased immune responsiveness. Consequently, the effects of relaxin and estradiol valerate, alone or in combination, were assessed in the development of adjuvant-induced arthritis in the rat. Combination hormone therapy reduced adjuvant-induced paw inflammation. Radiographic analysis of the tarsal joints showed that estradiol valerate plus relaxin treatment minimized soft tissue damage and bone changes when compared to vehicle-treated arthritic controls. These results indicate that relaxin may be a factor in reducing inflammation during pregnancy.

Gene deletion of either interleukin-1beta, interleukin-1beta-converting enzyme, inducible nitric oxide synthase, or stromelysin 1 accelerates the development of knee osteoarthritis in mice after surgical transection of the medial collateral ligament and partial medial meniscectomy.

OBJECTIVE: To investigate the development of osteoarthritis (OA) after transection of the medial collateral ligament and partial medial meniscectomy in mice in which genes encoding either interleukin-1beta (IL-1beta), IL-1beta-converting enzyme (ICE), stromelysin 1, or inducible nitric oxide synthase (iNOS) were deleted. METHODS: Sectioning of the medial collateral ligament and partial medial meniscectomy were performed on right knee joints of wild-type and knockout mice. Left joints served as unoperated controls. Serial histologic sections were obtained from throughout the whole joint of both knees 4 days or 1, 2, 3, or 4 weeks after surgery. Sections were graded for OA lesions on a scale of 0-6 and were assessed for breakdown of tibial cartilage matrix proteoglycan (aggrecan) and type II collagen by matrix metalloproteinases (MMPs) and aggrecanases with immunohistochemistry studies using anti-VDIPEN, anti-NITEGE, and Col2-3/4C(short) neoepitope antibodies. Proteoglycan depletion was assessed by Alcian blue staining and chondrocyte cell death, with the TUNEL technique. RESULTS: All knockout mice showed accelerated development of OA lesions in the medial tibial cartilage after surgery, compared with wild-type mice. ICE-, iNOS-, and particularly IL-1beta-knockout mice developed OA lesions in the lateral cartilage of unoperated limbs. Development of focal histopathologic lesions was accompanied by increased levels of MMP-, aggrecanase-, and collagenase-generated cleavage neoepitopes in areas around lesions, while nonlesional areas showed no change in immunostaining. Extensive cell death was also detected by TUNEL staining in focal areas around lesions. CONCLUSION: We postulate that deletion of each of these genes, which encode molecules capable of producing degenerative changes in cartilage, leads to changes in the homeostatic controls regulating the balance between anabolism and catabolism, favoring accelerated cartilage degeneration. These observations suggest that these genes may play important regulatory roles in maintaining normal homeostasis in articular cartilage matrix turnover.

Discovery of a potent and selective COX-2 inhibitor in the alkoxy lactone series with optimized metabolic profile.

The COX-2 inhibitor DFP [5,5-dimethyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone] was found to have a long half-life in humans. Analogues have been characterized in order to optimize pharmacokinetics. This has lead to the discovery of 5(S)-(5-ethyl-5-methyl-3-(2-propoxy)-4-methanesulfonylphenyl)-2(5H)-furanone analogue 11 a potent and selective COX-2 inhibitor which is metabolized to a greater extent than DFP upon incubation with rat and human hepatocytes, suggesting a shorter half-life in humans.