Lisa Cheeks

Effect of Calcium Channel Blockers on Intraocular Pressure

We determined the effects of either topical or systemic calcium channel antagonists on rabbit intraocular pressure (IOP). Topical nifedipine, verapamil or diltiazem had no significant effect on IOP. Intravenous verapamil and nifedipine caused statistically significant reductions in IOP between 2 and 6 h after administration; the nifedipine response followed an increase in IOP at 30 min. Diltiazem, given 3 times daily for 3 days, caused no pressure change. In the rabbit, therefore, calcium channel antagonists have no effect when given topically, but do reduce IOP when given systemically.

Aqueous Humor Flow Rate and Intraocular Pressure during and after Pregnancy

Intraocular pressure and aqueous humor formation rate have been determined from the first trimester of pregnancy through term, with further determinations 3 months postpartum, in 7 patients. The intraocular pressure showed a consistent, statistically significant fall during pregnancy, returning to values seen in early pregnancy after delivery. Aqueous humor formation rate showed no change during pregnancy. The data indicate that the sustained elevated hormonal levels during pregnancy, either directly or indirectly, cause an increase in fluid outflow conductance from the eye without altering the rate of fluid entry.

Influence of vehicle and anterior chamber protein concentration on cyclosporine penetration through the isolated rabbit cornea.

The transcorneal penetration of cyclosporine A has been determined from each of three vehicles across isolated cornea into simulated aqueous humor containing either 50 mg % protein (0.5 mg/ml; as found in a normal eye) or 5000 mg % protein (50 mg/ml; as found in an inflamed eye). Cyclosporine entered the corneal epithelium and stroma/endothelium as well as passed through the cornea from an alpha cyclodextrin vehicle. Entry into the epithelium and stroma/endothelium occurred from an ointment vehicle with limited detectable anterior chamber penetration using 50 mg % protein solution in the anterior chamber. From corn oil vehicle, cyclosporine penetrated across the cornea with a permeability equal to that of alpha cyclodextrin vehicle. The concentration of cyclosporine in both corn oil and ointment vehicles is 8 times greater than that in alpha cyclodextrin vehicle resulting in a flux from corn oil vehicle about 7 or 8 times greater than that seen after alpha cyclodextrin vehicle. The amounts retained in the cornea, however, were relatively low after corn oil compared to cyclodextrin. The penetration of cyclosporine from either the cyclodextrin vehicle or ointment was at least doubled in the presence of 5000 mg % protein in the simulated aqueous humor relative to that seen in 50 mg % protein. This data indicates that the (presumed) absorption and binding of drug by the excess protein in the simulated aqueous humor may have removed free cyclosporine from the solution and sustained a high concentration gradient of free solute across the cornea.(ABSTRACT TRUNCATED AT 250 WORDS)

Detergent penetration into young and adult rabbit eyes: comparative pharmacokinetics

AbstractThe ocular penetration and pharmacokinetics of two anionic (sodium lauryl sulfate [12-carbon chain] and an ethoxylated alkyl sulfate [18-carbon chain]) and one cationic (benzalkonium chloride) surfactant are compared with those of other ophthalmic drugs. Where possible, these comparisons are made between albino and pigmented and young and adult rabbits. There are significant differences between young and adult rabbits, both in terms of the mass of detergent entering the various tissue and fluid compartments of the eye and in the pharmacokinetics of surfactants in the two age groups. The differences between the C-18 and C-12 chain anionic detergents is pronounced, with the C-18 compound being retained for longer times. Young animals amass greater quantities of detergents per unit tissue weight. The cationic detergent does not enter the ocular fluids or internal tissues, being confined to the conjunctiva and cornea. Both anionic and cationic detergents show a very slow turnover once within the ocula...

Drug interaction with intraocular lenses of different materials

ABSTRACT The uptake and washout kinetics of four drugs representing different classes of ophthalmic medications were measured in intraocular lenses of different materials. The materials ranged from hydrogel lenses to poly(methyl methacrylate) (PMMA), Acrysof™ (acrylic/methacrylic), and two types of silicone lenses (Chiroflex and AMO SI‐18NB). Uptake was determined after seven days of immersion in a large volume of Ringers solution containing drug concentrations that equaled those found in aqueous humor 30 minutes to one hour after topical administration. Washout was determined after placing lenses in 1 ml of 0.9% saline for 24 hours. Only hydrogel lenses could be digested in acid to measure lens uptake directly. The PMMA, Acrysof, and silicone lenses behaved similarly toward gentamicin and dexamethasone—low uptake (< 3.5 ng/mg lens) and low washout (< 4.0%). Their uptake of norepinephrine was lower (< 0.7 ng/mg lens) but the washout varied from 29% (AMO silicone) to 100% (PMMA and Acrysof). The pilocarpine uptake was the lowest of drugs tested (< 0.03 ng/mg lens) and the washout varied from 1.5% (acrylic) to 100% (PMMA and Chiroflex silicone). Hydrogel lenses took up the most drug in the following order: dexamethasone > pilocarpine > gentamicin > norepinephrine. Washout was high, ranging from 83% to 98%. Despite the greater uptake and washout, the maximum drug uptake would only provide one‐tenth of the greatest aqueous humor concentration that occurs after topical drug administration. Intraocular lenses of the materials tested did not interfere with the intraocular drug pharmacokinetics, nor did the data indicate that presoaking intraocular lenses of these materials in drugs would enhance post‐surgical intraocular drug concentrations.

Subconjunctival Gentamicin Induction of Extraocular Toxic Muscle Myopathy

Subconjunctival injection of commercially available gentamicin, delivered in one of several protocols, caused an acute toxic reaction myopathy of the extraocular muscles. The response began as a small focal infiltrate of polymorphonuclear leukocytes, and as the lesion progressed it assumed a mononuclear cell predominance accompanied by muscle fiber degeneration. The injection of individual components of the commercial preparation (gentamicin, methylparaben, ethylenediaminetetraacetic acid (EDTA) and sodium bisulfite), each at the same concentration as in the parent solution, gave no response except for gentamicin alone. Gentamicin caused acute toxic myopathy when injected away from the muscles and when given as an isotonic solution in saline compared to the hypotonic commercial solution. Solutions at acidic pH not containing gentamicin did not initiate myopathy. Several factors that have been inferred as participating in the toxic response to gentamicin have been eliminated. Gentamicin alone is responsible for the induction of the extraocular muscle myopathy.

Corneal Endothelial Permeability after Anterior Chamber Silicone Oil

One of six silicone oils, differing in both viscosity and manufacture, was infused into the anterior chambers of rabbit eyes. Polydimethylsiloxane oil, 5000 cps, caused an increased corneal endothelial permeability to inulin and dextran at 24, 96, and 168 hours after placement into the eye. Intraocular pressures were slightly elevated in the experimental eyes, compared with contralateral controls, at 24 and 144 hours after infusion. The effects of five other oils on corneal endothelial permeability were examined 168 hours after infusion. All oils increased permeability and caused thinning of endothelial cells, together with the appearance of a retrocorneal membrane, except Dow Corning Medical Fluid 360. The results indicated that contact of most silicone oils with corneal endothelium rapidly induces physiologic and morphologic changes.

Ocular Blood Flow and Vascular Permeability in Endotoxin-Induced Inflammation

Blood flow was measured in several tissues of the rabbit eye following intravitreal injection of a dose of endotoxin that induces an inflammatory response. In separate experiments, the vascular permeability of the inflamed eye was estimated by iris fluorescein angiography and by measuring protein influx into the aqueous humor. The effect of topical corticosteroid treatment upon blood flow and vascular permeability was also measured. Following intravitreal endotoxin injection, minor changes in blood flow occurred in retina and optic nerve head. Marked changes were observed in blood flow in iris, ciliary processes, and choroid. Steroid treatment had no effect upon the increased blood flow 24 h after the endotoxin injection, although from a clinical standpoint the steroid-treated eyes appeared less inflamed. Fluorescein angiography demonstrated a massive increase in iris vessel permeability 6 and 24 h following endotoxin injection. Topical steroid treatment reduced fluorescein entry into the anterior chamber at both time periods. On the other hand, the increase in protein influx into the aqueous humor in the endotoxin-inflamed eye was not inhibited by steroid pretreatment. It is suggested that corticosteroids have a selective effect upon the permeability of different components of the blood-aqueous barrier, namely the ciliary processes and the iris vasculature.

Tear potassium contributes to maintenance of corneal thickness.

Isolated rabbit corneas were bathed on their endothelial surfaces with normal Krebs bicarbonate Ringer solution, while the epithelial surfaces were bathed in a basic tear solution containing sodium and potassium. When bathed in basic tear solution alone, corneal swelling occurred at an average of 12 microns/h over a 3-hour period. Corneal swelling occurred at a rate of about 21 microns/h when the epithelial solution was switched from normal basic tear solution to an iso-osmotic K(+)-free basic tear solution. Corneal swelling then slowed, and in the final hour of a 3-hour exposure to K(+)-free tear solution, the corneas deswelled at about 10 microns/h. The data indicate that potassium is a necessary solute for the maintenance of normal corneal thickness. The results suggest that a lacrimal dysfunction that would cause a decrease in the potassium content of tears may influence corneal thickness and also suggest that the inclusion of potassium in artificial tears is important.

Effects of calcium channel blockers on rabbit corneal endothelial function

The effects of calcium channel antagonists and agents that alter intracellular Ca2+ mobilization on corneal endothelial function have been examined. All experiments, except where specifically designated, were performed in the continuous presence of extracellular Ca2+. Verapamil (at 50 microM) increased the swelling rate of corneas bathed in normal Ringer solution whereas nifedipine and diltiazem (both up to 100 microM) were without effect. The nifedipine analog nisoldipine caused corneal swelling at 10 microM and 50 microM but nimodipine was without effect. When briefly exposed to a Ca(2+)-free solution corneal swelling was enhanced after subsequent exposure to 50 microM verapamil in normal Ringer but not after 50 microM diltiazem in normal Ringer, indicating that Ca2+ entry from the bathing solution into the cell was important and was apparently impeded by verapamil. Cadmium (0.6 and 1 mM) but not nickel (up to 250 microM) caused swelling of corneas bathed in normal Ringer. A Ca2+ channel agonist, BAY-K-8644, alone did not influence corneal thickness but when presented to the endothelium with 50 microM verapamil the swelling rate was much reduced compared to verapamil alone. The agonist, therefore, presumably maintained some Ca2+ channels open in face of the Ca2+ channel blocker. An agent that inhibited the release of intracellular Ca2+ stores (TMB-8) caused an initial corneal swelling over the first 1.5 hr of perfusion but thereafter had no effect on corneal thickness. In the presence of continued extracellular Ca2+ one explanation for the results is that modulation of intracellular Ca2+ by agents that alter plasma membrane transfer of Ca2+ influences apical junction permeability.(ABSTRACT TRUNCATED AT 250 WORDS)