Ocular Tissue Concentrations Research Articles

Heavy Metal Concentrations in Human Eyes

To measure the concentration of toxic heavy metals in the fluids and tissues of human eyes. Laboratory investigation. Thirty autopsy eyes of 16 subjects were dissected to obtain the aqueous, vitreous, lens, ciliary body, retina, and retinal pigment epithelium/choroid. Concentrations of lead, cadmium, mercury, and thallium in ocular tissues, ocular fluids, and blood were determined using an inductively coupled plasma-mass spectrometer and expressed as ng/g. Heavy metal concentrations in ocular tissues were compared using a paired t test. Lead and cadmium were found in all of the pigmented ocular tissues studied, concentrating to the greatest extent in the retinal pigment epithelium/choroid (mean, 432 +/- 485 ng/g and 2,358 +/- 1,522 ng/g). Cadmium was found in the retina in all eyes (mean, 1,072 +/- 489 ng/g) whereas lead was found in the retina in 9 (30%) of 30 eyes (mean, 53 +/- 54 ng/g). Trace concentrations of lead and cadmium were detected in the vitreous (mean, 0.5 +/- 1.0 ng/dl and 19 +/- 29 ng/dl), lens (mean, 13 +/- 18 ng/g and 20 +/- 18 ng/g), and blood (mean, 0.5 +/- 1.2 mug/dl and 3.1 +/- 4.1 mug/l) but were not detected in the aqueous. Mercury and thallium were not detected in any ocular tissues or fluids or in the blood. Lead and cadmium accumulate in human ocular tissues, particularly in the retinal pigment epithelium and choroid. The potential ocular toxicity of these heavy metals and their possible role in eye disease requires further study.

Effects of streptozotocin-induced type 1 diabetes mellitus on protein and ion concentrations in ocular tissues of the rat

This study investigated the effects of streptozotocin (STZ)-induced diabetes mellitus (DM) on protein and cation levels inocular tissues (lenses, cornea, lacrimal glands and retina with sclera) of rats. Diabetic rats and their lacrimal glands weighedsignificantly less (p < 0.05) than age-matched controls. Diabetic animals also had significantly (p < 0.05) elevated bloodglucose and significantly reduced (p < 0.05) plasma insulin compared to controls. Total protein concentrations in the cornea,lens, lacrimal gland and retina with sclera were markedly reduced compared to controls (circa 50%-90%). Diabetic cornea,lenses, lacrimal glands, and retina with sclera contained more Ca2+ (p < 0.05) than age-matched controls (2-3 fold). Levels ofZn2+ were also elevated (p < 0.05) in the cornea and retina with sclera of diabetic rats, as compared to control rats (2-3 fold),but were unaffected in lenses and lacrimal glands. In contrast, levels of Cu2+, Mg2+, Na+ and K+ were significantly reduced (p< 0.05) in all ocular tissues of diabetic rats when compared to control animals (circa 30%-70%). These results show thatSTZ-induced DM is generally associated with significant physiochemical changes in ocular tissues of rats with changesobserved in body weight, blood glucose, and insulin levels and protein and cation concentrations compared to healthy agematchedcontrols. Based on these data, it has been speculated that diabetes may induce changes in ocular tissues that include:higher protein turnover through increased protease activity and changes in Na+ / K+ channel function. It is suggested thatthese changes may be associated with diabetic retinopathy, diabetic cornea and sight impairment. (Int J Diabetes Metab13:154-158, 2005)

Grepafloxacin Concentration in Ocular Tissues after Intravenous Infusion in Rabbits with Intraocular Inflammation

Purpose: To determine the penetration of grepafloxacin into ocular tissues during experimental ocular inflammation. Methods: 10 albino and 10 pigmented rabbits underwent a continuous intravenous infusion of the drug 24 h after injecting Salmonella typhimurium toxin intravitreously, creating ocular inflammation. The animals were killed and grepafloxacin levels were determined in plasma and ocular tissues using high performance liquid chromatography. Results: Grepafloxacin levels achieved a steady-state plasma concentration of 1.5 µg/ml. The drug diffused more towards vascularized tissues (chorioretina and iris) in both albino and pigmented rabbits with a tissue/serum ratio higher than 1. Grepafloxacin showed more affinity to pigmented tissue, rising levels of 40,000–50,000 ng/g in the chorioretina and iris in pigmented animals. After inflammation, grepafloxacin intraocular penetration increased in albino animals with levels exceeding the minimum inhibitory concentration for the most common ocular pathogens. Conclusion: Grepafloxacin intraocular penetration is higher in pigmented tissues. Ocular inflammation increases the drug penetration into the vitreous.

Iontoforese no transporte ocular de drogas

O método mais comum de administração de drogas no olho é por meio de colírios. Entretanto, por este método, não é possível atingir a concentração terapêutica nos fluidos e tecidos posteriores do olho. A administração sistêmica apresenta reduzido acesso ao segmento posterior do olho devido à presença das barreiras oculares. Injeções subconjuntivais e retrobulbares não são capazes de proporcionar níveis adequados da droga, e a injeção intravítrea é método invasivo, inconveniente e que apre-senta riscos de perfuração do bulbo ocular ou descolamento da retina. A iontoforese, no entanto, apresenta-se como alternativa para o transporte de doses terapêuticas de drogas para o segmento posterior do olho. A iontoforese é uma técnica que consiste na administração de drogas para o organismo através dos tecidos, utilizando um campo elétrico. O eletrodo ativo, que se encontra em contato com a droga, é colocado no local a ser tratado, e um segundo eletrodo, com a finalidade de fechar o circuito elétrico, é colocado em outro local do organismo. O campo elétrico facilita o transporte da droga, que deve se encontrar, preferencialmente, na forma ionizada. A iontoforese pode ser considerada como um método seguro e não invasivo de transporte de drogas para locais específicos do olho. Aplicada experimentalmente para o tratamento de doenças oculares, esta técnica tem evoluído muito nos últimos anos e, atualmente, testes clínicos de fase III encontram-se em andamento.

Ocular pharmacokinetic/ pharmacodynamic modeling for bunazosin after instillation into rabbits.

To develop a pharmacokinetic/pharmacodynamic (PK/PD) model for an alpha1-blocker (bunazosin) after instillation. The PK/PD model can predict both the drug concentrations in various ocular tissues and the hypotensive effect. Bunazosin concentrations were determined with High Performance Liquid Chromatography (HPLC) in tear fluid, the aqueous humor, cornea, and iris-ciliary body after instillation or ocular injection into the anterior chamber in rabbits. After instillation of bunazosin in rabbits, intraocular pressure (IOP) was also determined with a pneumatic tonometer. The PK/PD parameters were estimated by fitting the concentration-time profiles and the hypotensive effect-time profiles to the developed PK/PD models using the MULTI (RUNGE) program. On the basis of the concentration-time profiles of bunazosin, a PK model, including seven compartments, was developed for examining the behavior of bunazosin after instillation. Then, two PK/ PD models for hypotensive effect of bunazosin were developed using an indirect response (model A) and the relationship between IOP and aqueous humor flow (model B). These models well described the concentration-time profiles and hypotensive effect-time profiles of bunazosin after instillation. This study is the first trial to develop a PK/PD model for an antiglaucoma agent using an indirect response and the relationship between IOP and aqueous humor flow.

Effects of Dorzolamide Hydrochloride on Ocular Tissues

We studied the intraocular pharmacokinetics of dorzolamide hydrochloride eye drops and the effect of dorzolamide on carbonic anhydrase activity and localization in ocular tissues. Carbonic anhydrase activity was detected in normal ocular tissues. The activity was inhibited in corneal endothelial cells, the ciliary body, lens epithelial cells, or the retina 1 to 8 hours after instillation of dorzolamide eye drops. In lens epithelial cells and the retina, the enzyme activity had not recovered even 10 hours after instillation of the drug. Immunostaining did not reveal any differences between the group administered dorzolamide eye drops and the control group administered a physiologically balanced solution. Time-related changes in dorzolamide concentrations in ocular tissues were measured by high-performance liquid chromatography (HPLC). In the cornea, anterior aqueous, iris, ciliary body and retina, drug concentrations increased 15 minutes after the instillation and peaked within 1 hour. These results suggest that dorzolamide immediately suppresses carbonic anhydrase activity in ocular tissues, and is rapidly distributed among the tissues of the eye when administered as eye drops.

Pharmacokinetic profile of topical flunarizine in rabbit eye and plasma.

The purpose of this study was to determine the aqueous humor, cornea, iris-ciliary body, retina and plasma levels and pharmacokinetics of a new topical formulation containing 0.05% flunarizine upon single drop application. Albino rabbits were used and tissue samples were collected at 15, 30, 60, 120 and 240 min after instillation. Drug concentrations in ocular tissues and plasma were measured by gas chromatography assay. After single dose application peak levels of drug were achieved at 15 min in cornea and at 30 min in aqueous humor, iris-ciliary body and retina. Unilateral topical flunarizine caused a significant reduction of intraocular pressure in rabbits. The pharmacokinetic profile showed a good ocular bioavailability of the drug providing that the new topical formulation containing 0.05% flunarizine reach the target tissues at effective concentrations and therefore may be use in the treatment of glaucoma.

The Distribution Kinetics of Topical14C‐Sulfur Mustard in Rabbit Ocular Tissues and the Effect of Acetylcysteine

Sulfur mustard (2,2‐dichlorodiethyl sulfide; HD), is a potent alkylating agent which in liquid or vapor form is capable of causing severe injuries to skin and respiratory tract, and was shown to cause short‐ and long‐term ocular injuries. N‐Acetylcysteine (NAC) may act as a mucolytic agent, changing the “wetting” and scavenging properties of the cornea and thus the adhesion of HD. Moreover, NAC is a scavenger of HD, an antioxidant and a glutathione precursor, which was shown to reduce HD toxicity in various systems. The ocular distribution of 14C, after topical application of liquid 14C‐sulfur mustard (14C‐HD) to the rabbit cornea, and the role of NAC in reducing HD retention and toxicity are presented in this study. Groups of rabbits were exposed to 0.4 µL of liquid 14C‐HD, placed at the center of the cornea, with or without NAC treatment. Fifty µL NAC (10% aqueous solution) was topically applied, 10 minutes before and 10 minutes after HD exposure. Three time points were evaluated: 1, 6, and 24 hr after HD exposure, six rabbits per time point. Evaluation consisted of clinical observation, measurement of biochemical parameters in aqueous humor (AQ), counting radioactivity concentration in ocular tissues, and histology of corneal sections. One hour after corneal exposure to liquid 14C‐HD, approximately 2% of total applied radioactivity was recovered. The highest 14C concentration was found in the cornea, followed by the tarsal section of eyelid, aqueous humor, nictitating membrane, and the frontal sclera (including conjunctiva). The rate of radioactivity decrease varied from one ocular tissue to the other, the highest rate was found in aqueous and vitreous humors, also in accordance with their higher turnover rates. The NAC treatment reduced the radioactivity in most ocular tissues. The HD exposure caused typical clinical and histological signs of HD intoxication, and increased the aqueous protein and prostaglandin (PGE) content. The NAC treatment lowered eyelid edema but had no effect on AQ protein or PGE content; however, there was some aggravating effect of the NAC treatment on corneal epithelial cells, seen at 1 and 6 hr after exposure.

The pulsatile ocular blood flow behaviour in open angle glaucoma patients after replacing timolol therapy with timolol and dorzolamide fixed combination: preliminary study.

The role of ocular perfusion in the pathogenesis of primary open angle glaucoma (POAG) is increasingly discussed. At present topical beta-blockers are the most common treatment in glaucoma but almost half the patients on this topical beta-blocker treatment require an adjunct therapy to control the glaucomatous damage progression (Centofanti et al. 1999). Dorzolamide, a topical CA inhibitor, is one of the drugs most used in addition to beta-blocker therapy. This drug inhibits CA-ll isoenzyme, which plays an important role in the aqueous humour production in humans. Topically applied, dorzolamide increases retinal blood flow velocity in normal tension glaucoma patients (Sugrue 2000), enhancing CO2 concentration in ocular tissues. Scanning laser ophthalmoscopy demonstrated how dorzolamide accelerates blood velocity in the retinal and superficial optic nerve head without an apparent effect upon retrobulbar haemodynamics in healthy eyes (Harris et al. 1996). Moreover, dorzolamide accelerates retinal arteriovenous passage time of the fluorescein dye at constant retinal arterial and venous diameters, but failed to change flow velocities in any retrobulbar vessel in normal tension glaucoma patients (Harris et al. 1999). The aim of this study is to evaluate the pulsatile ocular blood flow (POBF) behaviour after adding topical anhydrase inhibitor dorzolamide in POAG patients in treatment with timolol 0.5% twice daily. Measurements of POBF, ocular pulse amplitude (PA) and intraocular pressure (IOP) were obtained by an ocular blood flow tonograph (Ocular Blood Flow System, OBF Laboratories, UK) in 12 POAG patients, 6 males and 6 females, mean age 67 years (aged between 59 and 75 years). with a well-controlled IOP using a timolol 0.5% twice-daily monotherapy. Heart rate, systolic and diastolic blood pressures were also measured at brachial artery. The first measurements were performed during the timolol 0.5% therapy before morning drop instillation (timolol trough) and 2 h after instillation (timolol peak). The second measurements were made after 2 weeks of timolol–dorzolamide fixed combination therapy and again before and after 2 h from the instillation (fixed combination trough and peak). A two-tailed paired Student's t-test was used to compare the timolol group to the fixed-combination group; P < 0.05 is considered significant. Data obtained at trough and peak during timolol monotherapy were compared to data, respectively, obtained at trough and peak during fixed combination therapy. We found a statistically significant IOP reduction at timolol peak compared to timolol trough (19.5 ± 3.1–17.9 ± 3.0 mmHg, −8.6%, P < 0.05, Table 1) and a statistically significant POBF increase at fixed combination peak compared to timolol peak (705.3 ± 234–769.0 ± 289 µl/min, + 8.7%, P < 0.05, Table 2). Other variables examined did not show any statistically significant change. In this study we found no statistically significant differences in IOP reduction between timolol 0.5% monotherapy and timolol–dorzolamide fixed combination therapy either at trough or at peak. The addition of dorzolamide to timolol monotherapy brought about an increase of POBF values which may be attributed to a direct action of the topical anhydrase inhibitor independently of IOP changes. The increasing of POBF without any statistical significant change of systemic blood pressure and heart rate leads to these variables not being considered as possible factors responsible for ocular perfusion improvement. Studies have shown that timolol–dorzolamide fixed combination efficacy in reducing IOP is completely comparable to the same combination given separately (Sugrue 2000) (not fixed). The advantage is a reduction in the number of daily instillations (from 4 to 2) associated with improved patient compliance. Therefore our results confirm the valid effect of dorzolamide action on ocular blood flow in POAG patients.

Timolol concentrations in rat ocular tissues and plasma after topical and intraperitoneal dosing.

Topical beta-blockers, such as timolol, have been used extensively in the medical treatment of glaucoma to lower intraocular pressure (IOP). Recently, these drugs have been shown to have effects on the retinal and optic nerve circulation as well as potential neuroprotective properties. In the current study, the concentration of timolol attained in the cornea, iris-ciliary body, retina, vitreous, and plasma was measured after topical or intraperitoneal administration in rats to determine the relative contributions of each route to intraocular timolol concentrations. One group of rats received one drop of commercially available 0.5% timolol in the right eye and two drops in the left eye for 3 to 12 days. Another group of rats received one drop of 0.5% timolol in one eye only and concentrations were studied in the ocular tissues at 15, 30, 60, 120, and 240 minutes after instillation. The final group of rats received a single intraperitoneal injection of timolol ranging in concentration from 5 to 75 mg/kg after which tissue and plasma concentrations were measured 30 minutes after injection. All tissue and plasma concentrations were measured by high performance liquid chromatography. Rats that received topical timolol daily for 3 to 12 consecutive days accumulated timolol concentrations of 2.3 to 4.4 microg/g in cornea, 198 to 326 microg/g in iris, 0.05 to 0.11 microg/ml in vitreous, and 0.17 to 0.77 microg/g in retina. In rats that received a single drop of timolol in one eye, the tissue concentrations were higher in the treated eye than in the untreated eye in all cases except for vitreous. In these experiments, timolol levels in plasma were either low or not detectable. Increasing timolol doses administered intraperitoneally resulted in corresponding increased tissue and plasma concentrations. Absorption of drug into the systemic circulation plays a significant role in delivering timolol to the retina and vitreous in addition to a local ocular route. A clear dose-response relationship exists in all ocular tissues studied after an intraperitoneal dose of timolol. High doses of timolol were required to achieve measurable concentrations of drug in the ocular tissues via our high performance liquid chromatography assay suggesting that a significant hepatic first-pass effect may be involved after an intraperitoneal injection of timolol.

Distribution of brimonidine into anterior and posterior tissues of monkey, rabbit, and rat eyes.

The objectives of the study were to evaluate the distribution of brimonidine (alpha2-adrenergic agonist) into anterior and posterior ocular tissues. Single or multiple doses of a 0.2 or 0.5% brimonidine tartrate solution were administered to one or both eyes of monkeys or to one eye of rabbits. Brimonidine was administered intraperitoneally to rats. After topical administration, [14C]brimonidine was rapidly absorbed into the cornea and conjunctiva and distributed throughout the eye. [14C]Radioactivity was higher and cleared more slowly in pigmented tissues (iris/ciliary body, choroid/retina, and optic nerve) than in nonpigmented tissues. Single and multiple dosing led to a similar drug distribution, with higher levels of brimonidine measured in pigmented tissues after multiple dosing. Most of the radioactivity extracted from ocular tissues represented unchanged brimonidine. In the rabbits and the monkey treated in only one eye, levels of radioactivity in the untreated eye were low, consistent with the low systemic levels and rapid drug clearance. Posterior ocular tissue concentrations of radioactivity exceeded systemic blood concentrations. The vitreous humor brimonidine concentrations in monkeys treated topically with 0.2% brimonidine tartrate was 82 +/- 45 nM. Vitreous levels in rabbits confirmed the penetration of brimonidine to the posterior segment. Similar concentrations of brimonidine (22 to 390 nM) were measured in the vitreous and retina of rats injected intraperitoneally with brimonidine. Both topically applied and systemically administered brimonidine reach the back of the eye at nanomolar concentrations sufficient to activate alpha2-adrenergic receptors. The brimonidine levels achieved at the retina are relevant for neuroprotection models.

Slow release of acetylsalicylic acid by intravitreal silicone oil.

To assess in vitro the potential of silicone oil as a delivery system for acetylsalicylic acid (ASA) and to evaluate in vivo the pharmacokinetic distribution of salicylic acid (SA) in the eye. In an experimental model ASA/silicone oil suspension mixed to a concentration of 1.67 mg/mL was investigated for release rate of ASA and SA. In vivo vitrectomy and intravitreal injection of two different ASA/silicone oil suspensions, both mixed to a concentration of 1.67 mg/mL, was performed on two groups, A and B, of New Zealand white rabbits. Salicylic acid concentrations in ocular tissues, aqueous, vitreous, and blood plasma were evaluated at 6 hours, 24 hours, and 5 days using high performance liquid chromatography. Salicylic acid was detected in all tissues. The highest levels were obtained in the vitreous: 745.4 microg/mL (A) and 640.0 microg/mL (B) at 6 hours. The retina followed with 332.9 ng/mg (A) and 281.3 ng/mg (B) at 6 hours and 31.6 ng/mg (A) and 48.1 ng/mg (B) at day 5. The maximum blood plasma levels were 5.2 microg/mL. Silicone oil is an efficacious delivery system of ASA in vitro and in vivo. Higher concentrations of SA were found in all ocular tissues and fluids when compared to intravenous administration of maximum doses.

Chitosan nanoparticles: a new vehicle for the improvement of the delivery of drugs to the ocular surface. Application to cyclosporin A

Present limitations in the management of extraocular diseases include the inability to provide long-term extraocular drug delivery without compromising intraocular structures and/or systemic drug exposure. In the present study, the potential of chitosan (CS) nanoparticles as a new vehicle for the improvement of the delivery of drugs to the ocular mucosa was investigated. Cyclosporin A (CyA) was chosen as a model compound because of its potential usefulness for the treatment of these local diseases. An ionic gelation technique was conveniently modified in order to produce CyA-loaded CS nanoparticles. These nanoparticles had a mean size of 293 nm, a zeta potential of +37 mV and high CyA association efficiency and loading (73 and 9%, respectively). In vitro release studies, performed under sink conditions, revealed a fast release during the first hour followed by a more gradual drug release during a 24-h period. In vivo experiments showed that, following topical instillation of CyA-loaded CS nanoparticles to rabbits, it was possible to achieve therapeutic concentrations in external ocular tissues (i.e., cornea and conjunctiva) during at least 48 h while maintaining negligible or undetectable CyA levels in inner ocular structures (i.e., iris/ciliary body and aqueous humour), blood and plasma. These levels were significantly higher than those obtained following instillation of a CS solution containing CyA and an aqueous CyA suspension. From these results, we can conclude that CS nanoparticles may represent an interesting vehicle in order to enhance the therapeutic index of clinically challenging drugs with potential application at extraocular level.

Distribution of lead and transthyretin in human eyes.

The retinal pigment epithelium serves as a defensive barrier to the retina in the same way that the choroid plexus functions in the brain. Previous studies have shown that lead sequestration in the choroid plexus reduces the production and secretion of transthyretin by the choroid plexus. The purpose of this study was to investigate the distribution of lead and transthyretin in human eyes and to explore the potential effect of lead on transthyretin in human eyes. Eight pairs of human eyes were obtained from the New York City Eyebank within 24 hours of postmortem. The eyes were dissected to obtain the aqueous, vitreous, retina, and choroid. Lead and transthyretin concentrations in ocular tissues and liquids were determined by atomic absorption spectrophotometry for lead and radioimmunoassay for transthyretin. Lead accumulated in the retina at concentrations that were 166, 739, and 5 times higher than those in the aqueous, vitreous, and choroid, respectively (p < 0.05 for all comparisons). Lead concentrations in ocular tissues or intraocular liquids did not change as a function of age or gender. The concentration of transthyretin in the vitreous (14.4 +/- 5.1 SE microg/mL) was twice as much as in the aqueous (7.0 +/- 1.1SE microg/mL) and was significantly correlated to that in the retina (r = 0.93, p < 0.005). This study indicates that lead accumulates in human ocular tissues, particularly in the retina. The markedly elevated retina lead level and its relationship to ocular transthyretin and other macromolecules bear further investigation.

Enhanced absorption and drug targeting by positively charged submicron emulsions

This overview presents the state of the art of positively charged submicron emulsions, their physicochemical properties, biofate, and therapeutic applications, especially for intravenous, ocular, and oral administration. The positive charge of submicron emulsions results from cationic excipients such as lipids, polymers, and surfactants in formulations. It was observed that positively charged submicron emulsions are stable in the presence of physiological cations and can interact in vivo with negatively charged biological membranes, resulting in an enhanced drug uptake and site-specific targeting. Numerous authors have shown that cationic emulsions can improve the oral bioavailability of lipophilic drugs and enhance drug permeation through cornea, leading to increased drug concentration in ocular tissues as compared to negatively charged submicron emulsions. In addition, positively charged oil droplets can accumulate markedly in the lung following i.v. injection, opening new therapeutic possibilities for lung cancer chemotherapy. Drug Dev. Res. 50:476–486, 2000. © 2000 Wiley-Liss, Inc.

Distribution of cyclosporin A in ocular tissues after topical administration to albino rabbits and beagle dogs

Purpose. To determine the ocular pharmacokinetics of cyclosporin A after topical ophthalmic administration. Methods. Radiolabled cyclosporin A in either a castor oil-in-water emulsion or a corn oil ointment was applied to the eyes of beagle dogs or albino rabbits using the following paradigms: (i) single doses of 0.2% emulsion to rabbits and dogs, (ii) single doses of 0.05%, 0.2%, or 0.4% emulsion to rabbits, (iii) multiple doses of 0.2% emulsion to dogs, (iv) single and multiple doses of 0.2% ointment to rabbits. The distribution of cyclosporin A was determined by measuring the distribution of radio-activity. Results. After a single dose, cyclosporin A was rapidly absorbed into the conjunctiva (C max : dogs, 1490 ng/g; rabbits, 1340 ng/g) and cornea (C max : dogs, 311 ng/g; rabbits, 955 ng/g). High concentrations (>300 ng/g) could be detected in the cornea up to 96 hours post-dose. Lower concentrations were found in the intraocular tissues, and systemic absorption was minimal. After multiple doses, there was some accumulation in the cornea, lens, lacrimal gland, and iris-cilliary body, but limited accumulation in the conjunctiva and sclera. Ocular tissue concentrations of cyclosporin A increased with increasing dose concentration; proportionally in lacrimal gland and intraocular tissues; less than proportionally in conjunctiva and cornea. The pharmacokinetic profile of the cyclosporin A corn oil ointment was similar to that of the emulsion. Conclusions. Topical ophthalmic cyclosporin A penetrated into extraocular tissues at concentrations adequate for local immunomodulation while penetration into intraocular tissues was much less and absorption into the blood was minimal.

Ocular Tissue Concentrations of Mitomycin C With Variable Dose and Duration of Application Time in Rabbits

We measured mitomycin C (MMC) concentrations in ocular tissues in rabbits with variable dose (0.1, 0.2, or 0.4 mg) and duration of application time (1, 3, or 5 minutes) of MMC using high-performance liquid chromatography. Mitomycin C concentrations at the administered site after single subconjunctival application of MMC and after irrigation showed significant correlation with dose and duration of time of application. By multiple regression analysis, MMC concentrations (μg/g) at the conjunctiva were described as −6.73 + 67.4 × Dose (mg) + 1.66 × Time (minutes) ( R 2 0.65); at the sclera, −1.85 + 38.2 × Dose + 0.927 × Time ( R 2 0.63); at the cornea, −0.727 + 8.44 × Dose ( R 2 0.46). With a 0.2-mg MMC dose, in all three application times (1, 3, or 5 minutes), MMC concentrations in the conjunctiva at the administered quadrant were three times higher than in the neighboring quadrants and 6 to 7 times higher than in the opposite quadrant. In the sclera, MMC concentrations were 3.5 times higher than in the neighboring sites and over 8 to 9 times higher than in the opposite site. In the cornea, MMC concentrations were 2 to 3 times higher than in the neighboring sites and opposite site. In the iris-ciliary body, MMC concentrations were 0.61 μg/g at the administered site with 0.2 mg for 3-minute application, 2 times higher than in neighboring sites, and 2 times higher than in opposite sites.

Selective boron accumulation in human ocular melanoma vs surrounding eye components after 10B1-p-boronophenylalanine administration. Prerequisite for clinical trial of neutron-capture therapy.

We have developed neutron-capture therapy (NCT) for cutaneous malignant melanoma using a melanoma-seeking 10B-dopa, analogue, 10B1-para-boronophenylalanine (10B1-BPA). In order to explore the feasibility of applying NCT further to ocular melanoma, we investigated the boron concentrations in ocular melanomas and normal ocular tissues by 10B1-BPA administration to three patients, because success of NCT depends mainly upon selective boron accumulation in melanoma. In the first and second ocular melanoma patients, to whom 10B1-BPA fructose complex (total dose of 10B1-BPA: 170 mg/kg body weight) was administered orally in two divided doses, the boron concentrations in blood, vitreous body, sclera and retina choroidea were lower than that in melanoma examined. In the third conjunctival melanoma patient, to whom 10B1-BPA fructose complex (dose of 10B1-BPA: 85 mg/kg body weight) was administered by intravenous drip infusion, the average boron concentration in four melanoma samples was 17.7 ppm, which was estimated to be within the range necessary for melanoma eradication by thermal neutron irradiation. Boron uptake by lens, vitreous body, retina choroidea and sclera was much lower than that by melanoma. It was suggested that such a superficial ocular melanoma as iris melanoma can be destroyed by NCT, although vision may be affected--mainly due to cataract formation.

Mitomycin Concentration in Rabbit and Human Ocular Tissues after Topical Administration

The authors measured mitomycin C (MMC) concentrations in ocular tissues with high-performance liquid chromatography. Mitomycin C concentration after a single subconjunctival injection of the drug in rabbit eyes showed a rapid decrease with a half-life of 0.18 to 0.30 hours for the conjunctiva and 0.20 to 0.45 hours for the sclera at the injection site. Irrigating the ocular surface with 200 ml of saline after MMC application reduced the initial drug concentration to one fifth in the sclera and to one fifteenth in the conjunctiva but did not change the half-life. The MMC concentration in human trabeculectomy specimens obtained immediately after MMC application (0.2 mg/0.5 ml) and irrigation was 5.4 to 12.0 micrograms/g with a mean of 8.4 micrograms/g, a level similar to that in the rabbit sclera immediately after the irrigation after administration of the same MMC dose. These results indicate that MMC disappears rapidly from the ocular tissues and that irrigating the tissues significantly reduces the tissue concentration of MMC.

Kinetics of uptake and effects of topical indomethacin application on protein concentration in the aqueous humor of dogs

Summary The pharmacokinetic properties of indomethacin and its effects on aqueous protein values were studied in 15 clinically normal Beagles. The dogs were treated every 6 hours with 1% indomethacin suspension in 1 eye, with the other eye serving as a control. After 24 hours, the dogs were anesthetized and samples of aqueous humor (ah) were drawn by aqueocentesis at 0, 15, 30, 60, and 90 minutes after initial paracentesis. Additional samples were drawn at the time of euthanasia, 180 (6 dogs) and 360 minutes (9 dogs) minutes after initial paracentesis. Blood samples were obtained at each treatment and at each aqueocentesis. The eyes were enucleated after dogs were euthanatized. Aqueous protein concentrations and indomethacin concentrations in ah, plasma, and different ocular tissues were determined. Topical indomethacin administration had no effect on baseline protein concentrations of ah. It reduced protein concentrations in ah significantly at all times after initial aqueocentesis. This reduction was approximately 30%. Indomethacin in the ah is mostly protein-bound. Concentrations were 350 ng/ml in primary ah and 1,305 ng/ml in secondary ah, 90 minutes after initial aqueocentesis. Free-drug concentrations were relatively constant at about 220 ng/ml. Indomethacin administered topically is readily absorbed by the ocular adnexae, reaching a steady-state concentration of 25 ng/ml in blood plasma 18 hours after the start of treatment. Plasma concentrations were 50 times lower than therapeutically effective concentrations. High indomethacin concentrations were found in the cornea only. Low concentrations were found in the iris and ciliary body, the lens, and in the choroid. On the basis of our findings, we conclude that topically administered indomethacin is effective in reducing protein concentrations in secondary ah and is rapidly eliminated from the eye.