The preparation of HEMA-MPC films for ocular drug delivery

There is a need to prolong drug residence time using a biocompatible formulation in the subconjunctival space after surgery to treat glaucoma. Drug releasing discs were prepared with 2-(hydroxyethyl)methacrylate (HEMA) and 2-methacryloyl-oxyethyl phosphorylcholine (MPC). The ratio of bound water (Wb) to free water (Wf) ratio increased from 1:0.3 to 1:6.8 with increasing MPC (0 to 50%, w/w). The optimal balance between water content, SR and mechanical strength were obtained with 10% MPC (w/w) hydrogels. Water-alcohol mixtures were examined to facilitate loading of poorly soluble drugs, and they showed greater hydrogel swelling than either water or alcohol alone. The SR was 1.2 ± 0.02 and 3.3 ± 0.1 for water and water:ethanol (1:1) respectively. HEMA-MPC (10%) discs were loaded with dexamethasone using either water:ethanol (1:1) or methanol alone. Drug release was examined in an outflow rig model that mimics the subconjunctival space in the eye. Dexamethasone loading increased from 0.3 to 1.9 mg/disc when the solvent was changed from water:ethanol (1:1) to methanol with the dexamethasone half-life (t½) increasing from 1.9 to 9.7 days respectively. These encouraging results indicate that HEMA-MPC hydrogels have the potential to sustain the residence time of a drug in the subconjunctival space of the eye

ABC-transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942.

The CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was upregulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin- and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use

Threshold Equivalence Between Perimeters

To determine equivalence between perimeters, 49 eyes of 35 subjects underwent static threshold testing of the central 30 degrees twice on each of three automated perimeters and twice by manual kinetic threshold testing with the Goldmann perimeter. The Octopus-Humphrey difference was 3.3 dB (2.3 dB in the upper two rows for programs 32 and 30–2). The Dicon-Octopus difference was 3.5 dB and the Dicon-Humphrey, 6.5 dB. The I4e stimulus of the Goldmann perimeter was equivalent to 17.1 dB, 13.6 dB, and 10.8 dB on the Humphrey, Octopus, and Dicon perimeters, respectively. The III4e stimulus of the Goldmann perimeter, used for visual impairment determination, was roughly equivalent to 7 to 10 dB, 4 to 7 dB, and 0 to 6 dB on the Humphrey, Octopus, and Dicon perimeters, respectively. The prediction when converting from one instrument to another was only 10% less reliable than the ability of a perimeter to predict the values on a second examination with the same perimeter. Validity of the conversion formulas was confirmed by the age-corrected normal values available for the Octopus, Humphrey, and Goldmann perimeters

Zonular Dialysis During Extracapsular Cataract Extraction in Pseudoexfoliation Syndrome

• Five patients with pseudoexfoliation syndrome (PES) and glaucoma developed extensive zonular dialyses during extracapsular cataract extractions. Weakness of the lens zonules or their attachments to the ciliary processes, which has been described in association with PES, may explain this complication. We believe that patients with PES are at particular risk for developing large zonular dialyses during extracapsular surgery. Preoperative phakodonesis, anterior chamber depth asymmetry, and excessive lens movement during the anterior capsulotomy should alert the surgeon to this problem

Glaucoma Filtering Surgery with 5-Fluorouracil

A life-table analysis of surgical outcomes was performed on the first eye of 155 patients who were enrolled in a pilot study of glaucoma filtering surgery with postoperative subconjunctival 5-fluorouracil (5-FU) injections. The success rates at 1-, 2-, and 3-year intervals were 68, 63, and 63%, respectively, for 88 patients with non-neovascular glaucoma in aphakia; 82, 75, and 75% for 39 patients with non-neovascular glaucoma after unsuccessful filtering surgery; and 68% at each yearly interval for 28 patients with neovascular glaucoma. Complications which resulted from filtering surgery and the 5-FU injections included corneal epithelial defects (55.5%), conjunctival wound leaks (36.8%), suprachoroidal hemorrhage (5.8%), rhegmatogenous retinal detachment (2.6%), endophthalmitis and phthisis (1.9% each), and corneal scarring, late bleb leak, malignant glaucoma, and traction retinal detachment (1.3% each). A Cox Model regression analysis failed to demonstrate a correlation between surgical success and age, race, type of filtering procedure, or total dose of 5-FU received. Postoperative subconjunctival 5-FU may increase the operative success rate for selected patients with a high risk for failure after glaucoma filtering surgery