piperidines and Dry-Eye-Syndromes

To evaluate safety and efficacy of topical ophthalmic tofacitinib (CP-690,550), a novel Janus kinase inhibitor, in treating dry eye disease (DED).. A phase 1/2 prospective, randomized, double-masked, multicenter, vehicle- and comparator-controlled trial (NCT00784719).. Patients (n = 327) 18 years of age and older with a DED diagnosis for 6 months or more.. Tofacitinib (0.0003% twice daily, n = 46; 0.001% in both eyes twice daily, n = 47; 0.003% twice daily, n = 48; 0.005% twice daily, n = 48; 0.005% once daily, n = 44) results were compared with those of groups receiving active treatment cyclosporine ophthalmic emulsion 0.05% twice daily (n = 47) and vehicle twice daily (n = 47). Safety and efficacy evaluations were performed at baseline and throughout the 8-week study.. Schirmer wetting, corneal staining, tear film break-up time, conjunctival staining, Ocular Comfort Index (OCI), and Ocular Surface Disease Index (OSDI).. All tofacitinib doses were well tolerated, exhibiting better patient-reported ocular tolerability than cyclosporine. For the proportion of patients achieving 10 mm or more Schirmer wetting (without anesthesia) at week 8 (primary end point), greater response rates were observed in the tofacitinib 0.001% twice daily (27.3%), 0.005% twice daily (25.5%), and 0.005% once daily (26.1%) groups versus vehicle (20.0%); however, the differences were not statistically significant. Mean increase in Schirmer wetting (without anesthesia) from baseline was statistically significant (P<0.2, 2-sided) for all tofacitinib doses (1.7-3.1 mm), cyclosporine (3.9 mm), and vehicle (1.4 mm). For corneal staining (total score), significant improvement (reduction) from baseline was observed for all tofacitinib doses (-0.9 to -1.9) and vehicle (-2.0), but not for cyclosporine. The proportion of patients with complete corneal clearing (CCC; 100%) at week 8 was greatest with tofacitinib 0.005% once daily (15.9%) versus vehicle (6.7%). Symptom scores (OCI, OSDI) at week 8 showed significant improvements from baseline for all tofacitinib groups, and tofacitinib demonstrated greater improvements than cyclosporine. The tofacitinib 0.005% once daily group showed significant improvements in both a sign (Schirmer wetting without anesthesia) and symptom (OSDI environmental triggers subscale) versus vehicle and also demonstrated the highest response rate for CCC (16.7%) at week 8.. This phase 1/2 study of tofacitinib demonstrated a trend for improving both signs and symptoms of dry eye. All doses of tofacitinib exhibited a reasonable safety profile and were well tolerated by patients with DED.

Topics: Cyclosporine; Double-Blind Method; Dry Eye Syndromes; Female; Humans; Janus Kinase 3; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Prospective Studies; Pyrimidines; Pyrroles; Surveys and Questionnaires; Tears; Treatment Outcome

To evaluate the immunomodulatory effect of topical ophthalmic tofacitinib (CP-690,550) after an 8-week treatment period in patients with dry eye disease (DED).. Biomarker substudy of a phase 1/2 prospective, randomized, vehicle- and comparator-controlled clinical trial (NCT00784719).. A total of 82 patients with moderate to severe DED enrolled.. Patients received 1 of 5 doses of tofacitinib (0.0003%, 0.001%, 0.003%, or 0.005% twice daily [BID] or 0.005% once daily [QD]), active comparator (cyclosporine ophthalmic emulsion, 0.05% [Restasis, Allergan Inc., Irvine, CA]), or vehicle control BID for 8 weeks. Conjunctival impression cytology and tear fluid samples were collected at baseline and after an 8-week treatment period. Conjunctival cells were analyzed by flow cytometry for human leukocyte antigen DR-1 (HLA-DR). Tear fluids were analyzed by microsphere-based immunoassays for tear levels of cytokines and inflammation markers.. Reduction in inflammation assessed by change from baseline in conjunctival cell surface level of HLA-DR and tear level of cytokines and inflammation markers.. At week 8, a decrease in conjunctival cell surface expression of HLA-DR was observed in patients treated with tofacitinib 0.005% QD and 0.003% BID: 71% and 67% of baseline, respectively, compared with 133% of baseline in patients treated with vehicle (P=0.023 and P=0.006, compared with vehicle, respectively). Matrix metalloproteinase (MMP)-3 in tears was reduced from baseline at week 8 (40% of baseline, P=0.035) in the tofacitinib 0.005% QD group, whereas the vehicle group showed 77% of baseline (P>0.20). Interleukin (IL)-1β in tears was 36% of baseline (P=0.053) in the tofacitinib 0.005% QD group and 95% of baseline (P > 0.20) in the vehicle group. Several other cytokines and inflammation markers in tears, including MMP-9, IL-15, IL-17A, and IL-12p70, were markedly reduced in the tofacitinib 0.005% QD group but not the vehicle group. There was an association between the changes in HLA-DR and the tear inflammation markers (P<0.05): HLA-DR with IL-12p70 (r=0.49) and IL-1β (r=0.46), IL-12p70 with IL-1β (r=0.90), and IL-17A with MMP-9 (r=0.82).. Topical ophthalmic tofacitinib may act as an immunomodulator in patients with DED. Treatment for 8 weeks showed a promising reduction of conjunctival cell surface HLA-DR expression and tear levels of proinflammatory cytokines and inflammation markers.

Topics: Administration, Topical; Conjunctiva; Cyclosporine; Cytokines; Dry Eye Syndromes; Female; Flow Cytometry; HLA-DR1 Antigen; Humans; Janus Kinase 3; Male; Middle Aged; Ophthalmic Solutions; Piperidines; Pyrimidines; Pyrroles; Tears

Five new drugs marketed within the last year that are used for medical problems often experienced by the elderly have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating system developed by the author (DAH). Advantages, disadvantages, and other important information regarding each new drug are identified and used as the basis for determining the rating. The drugs include two antidiabetic agents, an agent for gout, an antipsychotic agent, and a drug for dry eye disease.

Topics: Anti-Inflammatory Agents; Antipsychotic Agents; Drugs, Investigational; Dry Eye Syndromes; Gout Suppressants; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Peptides; Phenylalanine; Piperidines; Sulfones; Thioglycolates; Triazoles; Urea

Sjögren's syndrome is an autoimmune disease associated with inflammation of exocrine glands with clinical manifestations of dry eye and dry mouth. Dry eye in this disease involves inflammation of the ocular surface tissues - cornea and conjunctiva. While systemic blockade of adhesion molecules has been used to treat autoimmune diseases, the purpose of this study was to determine the therapeutic efficacy of topical application of an integrin α4 adhesion molecule antagonist in a mouse model of dry eye associated with Sjögren's syndrome. To assess this spontaneously developed ocular surface inflammation related to Sjögren's syndrome in TSP-1null mice (12 wks) was evaluated. Mice were treated with topical formulations containing 0.1% dexamethasone or 30 mg/ml GW559090 or vehicle control. Corneal fluorescein staining and conjunctival goblet cell density were assessed. Real-time PCR analysis was performed to assess expression of the inflammatory marker IL-1β in the cornea and Tbet and RORγt in the draining lymph nodes. Ocular surface inflammation was detectable in TSP-1null mice (≥12 wk old), which resulted in increased corneal fluorescein staining indicative of corneal barrier disruption and reduced conjunctival goblet cell density. These changes were accompanied by increased corneal expression of IL-1β as compared to WT controls and an altered balance of Th1 (Tbet) and Th17 (RORγt) markers in the draining lymph nodes. Topically applied dexamethasone and GW559090 significantly reduced corneal fluorescein staining compared to vehicle treatment (p = 0.023 and p < 0.001, respectively). This improved corneal barrier integrity upon adhesion molecule blockade was consistent with significantly reduced corneal expression of pro-inflammatory IL-1β compared to vehicle treated groups (p < 0.05 for both treatments). Significant improvement in goblet cell density was also noted in mice treated with 0.1% dexamethasone and GW559090 (p < 0.05 for both). We conclude that similar to topical dexamethasone, topically administered GW559090 successfully improved corneal barrier integrity and inflammation in an established ocular surface disease associated with Sjögren's syndrome.

Topics: Administration, Topical; Animals; Cell Count; Dexamethasone; Disease Models, Animal; Dry Eye Syndromes; Fluorescein; Glucocorticoids; Goblet Cells; Integrin alpha4beta1; Interleukin-1beta; Mice; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group F, Member 3; Ophthalmic Solutions; Phenylalanine; Piperidines; Real-Time Polymerase Chain Reaction; RNA, Messenger; Sjogren's Syndrome; Staining and Labeling; Thrombospondin 1

We investigated the effects of GW559090, a novel, competitive, and high-affinity α4 integrin antagonist, in a murine model of dry eye. Through interaction with vascular cell adhesion molecule 1 (VCAM-1) and fibronectin α4β1 integrin is involved in leukocyte trafficking and activation.. Female C57BL/6 mice, aged 6 to 8 weeks, were subjected to desiccating stress (DS). Bilateral topical twice daily treatment with GW559090 was compared to vehicle-treated controls. Treatment was initiated at the time of DS induction. Treatment effects were assessed on corneal staining with Oregon Green Dextran (OGD) and expression of inflammatory markers in ocular surface tissues by real time PCR. Dendritic cell activation was measured in draining cervical lymph nodes (CLN) by flow cytometry. Separate groups of mice received GW559090 subcutaneously to evaluate the effects of systemic administration on corneal staining and cells in CLN.. Topical GW559090 significantly reduced corneal uptake of OGD compared to vehicle-treated disease controls in a dose-dependent manner (1, 3, 10, and 30 mg/mL) with 30 mg/mL showing the greatest reduction in OGD staining. When administered topically, corneal expression of IL-1α, matrix metalloproteinase (MMP)-9, chemokine ligand 9 (CXCL9), and TGF-β1 was reduced in GW559090-treated eyes. Topical treatment with GW559090 decreased dendritic cell activation in lymph nodes. The effects on corneal staining and cellular composition in CLN were not reproduced by systemic administration of GW559090, suggestive of a local role for integrin antagonism in the treatment of dry eye.. The novel α4 integrin antagonist, GW559090, improved outcome measures of corneal staining and ocular surface inflammation in this murine model of dry eye. These results indicate the potential of this novel agent for the treatment of dry eye disease.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents; Biomarkers; Cell Adhesion; Cells, Cultured; Cornea; Dendritic Cells; Disease Models, Animal; Dry Eye Syndromes; Female; Flow Cytometry; Integrin alpha Chains; Integrin alpha4; Integrin alpha4beta1; Leukocytes; Mice; Mice, Inbred C57BL; Organic Chemicals; Phenylalanine; Piperidines; Vascular Cell Adhesion Molecule-1

To determine the effects of topical Janus kinase inhibition on ocular surface inflammation and immunity.. Ophthalmic 0.003% tofacitinib (CP-690,550) was administered topically to inhibit Janus kinase activation at the ocular surface. Male BALB/c mice 6 to 8 weeks of age were subjected to corneal thermocautery and randomized to receive tofacitinib, vehicle, or no treatment. Corneas were subsequently excised for fluorescence-activated cell sorting and quantitative real-time reverse transcription polymerase chain reaction. Female C57BL/6 mice 6 to 8 weeks of age were exposed to desiccating stress to induce experimental dry eye disease and randomized to receive tofacitinib, tofacitinib and vehicle, vehicle, or no treatment. Corneal fluorescein staining was performed to evaluate clinical disease severity. The corneas and conjunctivae were harvested for immunohistochemical staining and quantitative real-time reverse transcription polymerase chain reaction.. After corneal thermocautery, it was found that tofacitinib treatment decreased the corneal infiltration of CD45+, Gr-1+, and CD11b+ cells on days 1 and 3. Transcripts encoding interleukin (IL)-1β and IL-6 were significantly decreased by tofacitinib treatment at post-thermocautery day 3. In experimental dry eye disease, tofacitinib treatment twice per day significantly decreased corneal fluorescein staining on days 12 and 15. The corneal infiltration of CD11b+ cells was significantly decreased by tofacitinib treatment twice per day. Tofacitinib treatment twice per day significantly increased the corneal expression of IL-1RA, and significantly decreased the corneal expression of tumor necrosis factor and IL-23. Further, tofacitinib treatment twice per day significantly decreased the conjunctival expression of IL-17A and significantly increased the conjunctival expression of FoxP3.. Topical ophthalmic tofacitinib, a Janus kinase inhibitor, suppressed ocular surface inflammation and immunity in experimental corneal thermocautery and dry eye disease.

Topics: Adaptive Immunity; Administration, Topical; Animals; CD11b Antigen; Cell Movement; Cytokines; Disease Models, Animal; Dry Eye Syndromes; Female; Flow Cytometry; Gene Expression Regulation; Janus Kinase 3; Keratitis; Leukocyte Common Antigens; Leukocytes; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Ophthalmic Solutions; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Real-Time Polymerase Chain Reaction; Receptors, Chemokine