Journal of ocular pharmacology最新文献

The intent of this work was to examine the actions of allicin on 1) intraocular pressure (IOP) in normal and unilaterally sympathectomized (SX) rabbits; 2) cAMP accumulation in the rabbit iris-ciliary body (ICB) and cultured nonpigmented epithelial (NPE) ciliary body cells; and 3) 3H-norepinephrine (NE) release by calculating fractional tritium overflow in response to electrical field stimulation (EFS, 5 Hz, 12 V/cm) in isolated, perfused rabbit ICBs. Allicin, one of the active compounds produced by garlic, was evaluated on IOP and it was determined that allicin (1, 2.5, or 10 micrograms), topically, but not the precursor, alliin (10 micrograms), lowered the IOP unilaterally in normal rabbits. Allicin (10 micrograms) reduced the IOP by 6 +/- 1 mmHg (n = 4) in normal rabbits at 2 hrs (maximum response) whereas no change occurred in sympathectomized rabbit eyes. Moreover, allicin (0.01, 0.1, or 1 microM) caused 40, 40, or 52% inhibition, respectively, of 3H-NE overflow in response to EFS. Isoproterenol (ISO, 1 microM) stimulated cAMP accumulation by 3.6 and 9 fold in isolated rabbit ICB and cultured NPE cells, respectively. Allicin (1 microM) had no effect on basal cAMP level while it inhibited ISO-stimulated cAMP accumulation by 40% and 23% in ICB and NPE cells, respectively. This study suggests that allicin lowered IOP, in part, by dual actions at the neuroeffector junction.

In vitro permeability studies were conducted on isolated rabbit corneal membranes using aliphatic acyl esters of acyclovir to determine the effect of lipophilicity on the transcorneal diffusion. Corneal membrane permeability coefficients increased with increasing lipophilicity of the straight chain aliphatic esters. The branch chain ester, acyclovir isobutyrate, displayed an anomalously low corneal permeability when compared to acyclovir esters having similar molecular size and 1-octanol/water partition coefficient. In vivo corneal penetration studies were conducted on unanesthetized rabbits. The aqueous humor concentrations of acyclovir and the ester prodrugs were measured at twenty five minutes after the topical instillation of an aqueous solution of the appropriate compound. The concentration of acyclovir in the aqueous humor increased with increasing 1-octanol/water partition coefficient. The lipophilic modification was shown to have a greater effect on increasing productive corneal absorption than the precorneal loss pathways. The effectiveness of acyclovir butyrate as a treatment for primary herpetic keratitis was evaluated in the McKrae strain infected rabbit model. The compound did not lose activity due to the esterification of the 2' hydroxyl group.

Corneal transparency is maintained by an active transport system, located at the endothelial cell membranes. This bicarbonate-dependent pump counteracts the tendency of the corneal stroma to absorb water, swell and become opaque. Carbonic anhydrase inhibitors (CAI) are capable of attenuating the bicarbonate efflux, therefore causing thickening of the cornea. Eight novel sulfonamides were evaluated as potential probes for assessing the corneal endothelial functional reserves. Five of the six thiadiazoles and both benzothiazoles have demonstrated carbonic anhydrase inhibitory properties in vitro. Of the eight compounds tested, 2-ethyladipoyl-1,3,4-thiadiazole-5-sulfonamide (compounds III), 2-epoxy-1,3,4-thiadiazole-5-sulfonamide (compound V), and 2-acetamido-1,3,4-thiadiazole-5-N-methylsulfonamide (compound VI) have induced reversible corneal thickening. Although statistically significant (p < 0.05), the magnitude of the pachymetric effect did not exceed 6-10% of the total corneal thickness, probably because carbonic anhydrase (CA) is only one component of the active pump complex. The fact that a non-CAI (compound VI) was capable of inducing a reversible corneal thickening may suggest that other mechanisms are involved. Further studies will be conducted to identify a pharmacological agent capable of reversibly inhibiting the endothelial function in normal and diseased corneas, with a higher magnitude of effect.

A series of thiadiazole derivatives were topically applied in gels or suspensions to rabbits to determine their ocular hypotensive effect. As a result, the compounds with higher corneal permeabilities showed stronger effect in lowering IOP. In addition, gels also caused stronger effect than suspensions. Different concentrations of gel preparations produced diverse ocular hypotensive effects. A linear relationship between the integrated IOP response and logarithm concentration of inhibitor was found. It is proposed that the ocular hypotensive effect was attributed to the level of inhibitor in ciliary body.

Retinal ischemia was developed by occlusion of the central retinal artery for 30 minutes. The artery was reperfused thereafter, and the recovery of the b-wave amplitude was determined as an indication of the recovery of retinal function after ischemia. Following ischemia, it was found that dopamine antagonists, including chlofluperol, metoclopramide, trifluperol and droperidol, increased in b-wave amplitude recovery significantly over the control b-wave recovery. Similar effects were observed with haloperidol and loxapine, but to a lesser extent. The results correlated well with the improvement of retinal blood flow by these dopamine antagonists (4,5). Neither floropipamide, a dopamine antagonist, nor bromocriptine, a dopamine agonist, affected the b-wave recovery after ischemia. These results also correlate well with the inability of these agents to increase the retinal blood flow measured by the microsphere technique (4,5). These findings suggest that most of the dopamine antagonists, with the exception of floropipamide, could be used for the treatment and/or prevention of ischemic retinopathy.

We reported that in utero galactose-induced cataracts could be inhibited if aldose reductase inhibitors (ARIs) were included in the galactose diet of pregnant rats. These studies involved morphological and cytochemical approaches. We undertook this investigation to evaluate the effects of ARIs in preventing the formation, accumulation and depletion of dulcitol in lenses of in utero galactose exposed neonates and in mothers during and following pregnancy. Sprague Dawley rats were fed Purina Rat Chow with 50% galactose either with or without 15mg Sorbinil or 1mg Eisai compound E-0722/day/Kg body weight during and following pregnancy. The lenses of neonates and mothers were processed to determine dulcitol concentrations. At parturition there was a significant amount of dulcitol in the lenses of pups and their mothers, which reduced rapidly in the lenses of pups regardless of the diet fed to the nursing mother. While galactose had a cross-placental but not a milk-mediated effect, the ARIs had both cross-placental and milk-mediated effects on dulcitol accumulation and depletion, respectively. The galactose feeding of mothers post-parturition maintained the high lenticular dulcitol concentration and the absence of galactose led to a reduction in lenticular dulcitol. The correlation between dulcitol accumulation and cataract development is discussed.

Iontophoresis of methylene blue using pipette tip probes is an effective means of scleral staining in preparation for gonioscopic pulsed dye laser sclerostomy. The effects of the surface area of the pipette tip and of the duration of iontophoresis on the concentration and distribution of stain were investigated in rabbit eyes. Iontophoresis of 1% methylene blue was done using currents from 0.2 to 2.0 mAmp, pipette tip probes with surface areas from 0.02 to 7.1 mm2, and durations of iontophoresis from 0.5 to 10 minutes. Optimum iontophoresis parameters for delivering methylene blue to the eye were a current of 0.4 mA, a probe tip surface area of 0.19 mm2, and a duration of five minutes. The maximal scleral stain concentration, approximately 0.4%, was achieved using these optimal parameters. Microscopic analysis of frozen tissue sections demonstrated the stain to have penetrated the full thickness of the sclera after five minutes. Tissue samples were analyzed for dye 0.5, 2, 5, 12, and 24 hours after iontophoresis was completed. Decreased dye concentration by over 50% within 2 hours and complete disappearance of dye within 24 hours were demonstrated. Methylene blue concentration thresholds for laser ablation were also examined; the threshold of ablation of methylene blue was 0.0625% when an energy level of 75 mJ was used. We propose that iontophoresis of methylene blue is a useful adjunct to pulsed dye laser sclerostomy formation.

Although general anesthesia is frequently chosen for eye surgery or experimental studies of ocular blood flow, there are few data available describing its effects on ocular blood flow. In a previous study in cats, we reported that enflurane produced significant increases in preretinal oxygen tension, indicating an increase in oxygen availability in the retina. To examine whether this effect was due to an increase in retinal or choroidal blood flow, we used radioactively labeled 15 microns microspheres of Ce 141, Sn 113, Ru 103, or Nb 95, to measure ocular blood flow in cats during enflurane anesthesia. In 10 adult cats, retinal blood flow measured 75 +/- 13, 90 +/- 9 and 88 +/- 11 ml x 100 g-1 x min-1 (mean +/- S.E.M.) at 0.5, 1.0, and 1.5 MAC enflurane, respectively (1 MAC is the concentration at which 50% of subjects do not move in response to a standardized stimulus). Corresponding values for choroidal blood flow were 1275 +/- 124, 876 +/- 106 and 842 +/- 102 ml x 100 g-1 x min-1 (mean +/- S.E.M.) at 0.5, 1.0, and 1.5 MAC enflurane, respectively. The decrease in choroidal blood flow was significant between 0.5 and 1.0 MAC. These results differ from those in our previous investigation of the effects of halothane on ocular blood flow. With halothane, retinal blood flow increased and choroidal blood flow decreased throughout the entire dose range (0.5, 1.0, and 1.5 MAC). We conclude that inhalational anesthetic agents produce significant but different effects upon ocular blood flow.

We have previously shown the pharmacokinetic value of delivering gentamicin to the rabbit anterior segment using the Morgan Therapeutic Lens. The present study utilized an intrastromal injection model of Pseudomonas keratitis to test the therapeutic efficacy of continuous flow delivery of gentamicin with the Morgan therapeutic lens. All eyes (n = 52) received an intrastromal injection of approximately 1800 colony forming units (CFU) of Pseudomonas aeruginosa. At 22 hours after injection, eyes were perfused for 6 hours with saline or gentamicin (1, 2.5 or 5 mg/ml), or received gentamicin drops (13.6 mg/ml) at 15 minutes for four doses, then hourly for 6 hours. Corneas were homogenized and plated to determine bacterial survival, and expressed as log colonies (CFU). Log CFU recovered were 7.37 +/- 0.04, 6.64 +/- 0.20, 5.64 +/- 0.31, and 3.56 +/- 0.50 log CFU for saline perfusion, 1, 2.5, 5 mg/ml gentamicin perfusion respectively. Following six hours of treatment with topical fortified gentamicin drops, 5.93 +/- 0.34 log CFU were recovered. Gentamicin perfusion (5 mg/ml) was significantly different from saline or the other treatment groups (P < 0.05). Continuous corneal perfusion with the Morgan Therapeutic Lens demonstrated an increasing dose response curve with increasing perfusate concentration. It was effective in the treatment of experimental Pseudomonas keratitis.

It has been reported that some dopamine antagonists can suppress the intraocular pressure and can increase the blood flow in the retina and choroid. Therefore, several dopamine antagonists and agonists were studied to determine if they can increase the ocular pulsatile blood flow in ocular hypertensive rabbits with the intraocular pressure raised artificially to 40 mm Hg. It was found that numerous dopamine antagonists including loxapine, moperone, domperidone, haloperidol and metoclopramide increased pulsatile blood flow for 49-110%, 95-155%, 72-86%, 60-114%, and 39-139%, respectively. Floropipamide reduced the ocular pulsatile blood flow for 18% at 90 min and 10% at 120 min. Chlofluperol produced biphasic action on pulsatile blood flow by significantly reducing it initially at 60 min (-49%) and then markedly increasing it at 180 min (91%). In case of dopamine agonists, neither dopamine nor bromocriptine affected the pulsatile blood flow significantly. These results indicate that some of dopamine antagonists could be used to lower the intraocular pressure and to increase the ocular pulsatile blood flow as well.