Difluprednate versus prednisolone acetate for inflammation following cataract surgery in pediatric patients: a randomized safety and efficacy study.

PurposeTo evaluate safety and efficacy of difluprednate 0.05% ophthalmic emulsion for treatment of postoperative inflammation after cataract surgery in pediatric patients.MethodsThis was a phase 3B, multicentre, randomized, double-masked, active-controlled study of patients aged 0-3 years who underwent uncomplicated cataract surgery in one eye, with/without intraocular lens implantation. Patients were randomized to receive difluprednate 0.05% four times daily or prednisolone acetate 1% for 14 days post surgery, followed by tapering for 14 days. Safety included evaluation of adverse events. Primary efficacy was the proportion of patients with an anterior cell grade of 0 (no cells) at day 14; secondary efficacy was a global inflammation score.ResultsForty patients were randomized to each treatment group. Adverse drug reactions included corneal oedema (difluprednate 0.5%, n=1; prednisolone acetate 1%, n=0) and increased intraocular pressure or ocular hypertension (n=2/group). Mean intraocular pressure values during treatment were 2-3 mm Hg higher with difluprednate 0.05% compared with prednisolone acetate 1%; mean values were similar between groups by the first week after treatment cessation. At 2 weeks post surgery, the incidence of complete clearing of anterior chamber cells was similar between groups (difluprednate 0.05%, n=30 (78.9%); prednisolone acetate 1%, n=31 (77.5%). Compared with prednisolone acetate 1%, approximately twice as many difluprednate 0.05%-treated patients had a global inflammation assessment score indicating no inflammation on day 1 (n=12 (30.8%) vs n=7 (17.5%) and day 8 (n=18 (48.7%) vs n=10 (25.0%).ConclusionsDifluprednate 0.05% four times daily showed safety and efficacy profiles similar to prednisolone acetate 1% four times daily in children 0-3 years undergoing cataract surgery.

Histamine induced contraction of human ciliary muscle cells.

In cultured human ciliary muscle cells we previously showed that histamine, via an H1 receptor, stimulates the production of inositol phosphates and mobilization of intracellular calcium. We further investigated in this study whether histamine would cause contraction of human ciliary muscle cells. Photomicrographs were taken of the ciliary muscle cells before and after exposure to histamine. Cross sectional surface area of the cells was quantified using image analysis software. A decrease in cross sectional surface area was interpreted as an indication of cell contraction. The results of this study indicated that histamine (10(-6) M-10(-4) M) caused contraction of human ciliary muscle cells in a concentration-dependent fashion. The effect of histamine was mediated by the H1 receptor subtype since the histamine effect was antagonized by 10(-6) M chlorphentramine (an H1 receptor subtype selective antagonist) but not by 10(-6) M cimetidine (H2 antagonist) or thioperamide (H3 antagonist). The phospholipase C (PLC) inhibitor, U73122 (10(-6) M) and the intracellular calcium store depleting agent thapsigargin (10(-6) M) both prevented the histamine induced contraction, demonstrating that the activation of PLC and the intracellular calcium release were the key steps necessary for contraction. Our data indicate that in ciliary muscle cells, histamine, via an H1 receptor, activates PLC and increases intracellular calcium, which subsequently causes contraction of the cells.

Effect of histamine on phosphoinositide turnover and intracellular calcium in human ciliary muscle cells.

This report describes the effect of histamine on phospholipase C (PLC) activity and calcium mobilization in cultured human ciliary muscle cells. PLC activity was assessed by measuring the production of inositol phosphates and intracellular calcium mobilization was assessed by Fura 2 ratio fluorometry. The stimulation of PLC by histamine was concentration dependent with an EC50 of 0.96 microM. The H1 antagonist chlorpheniramine blocked the response with an IC50 of 0.53 microM. Calcium fluorometry experiments indicated a mean basal calcium concentration of 36 nM with a 10(-4) M histamine induced mean peak value of 1132 nM followed by a gradually declining plateau phase. EC50 and IC50 (chlorpheniramine) values from histamine induced peak calcium concentrations agreed with the PLC results. Pretreatment of the cells with the PLC inhibitor U73122 at 10(-6) M completely blocked histamine induced calcium mobilization. Removal of extracellular calcium eliminated the plateau phase but not the initial calcium peak indicating that both intra and extracellular calcium sources are required for a normal response. The calcium ATPase inhibitor thapsigargin caused depletion of intracellular calcium stores and prevented a subsequent normal calcium mobilization response to histamine. Ryanodine, a release inhibitor of certain intracellular calcium stores, had no effect on the histamine induced response. The results of these experiments indicate that histamine, via an H1 receptor, activated the PLC second messenger pathway, and caused a multi-phasic mobilization of both intracellular and extracellular calcium. The entry of the extracellular calcium was shown to be dependent upon release of calcium from a ryanodine insensitive intracellular store.