Transcorneal Iontophoresis Research Articles

New Perspectives for Eye-Sparing Treatment Strategies in Primary Uveal Melanoma.

Simple SummaryUveal melanoma is the most common intraocular cancer. The current eye-sparing treatment options include mostly plaque brachytherapy. However, the effectiveness of these methods is still unsatisfactory. In this article, we review several possible new treatment options. These methods may be based on the physical destruction of the cancerous cells by applying ultrasounds. Another approach may be based on improving the penetration of the anti-cancer agents. It seems that the most promising technologies from this group are based on enhancing drug delivery by applying electric current. Finally, new advanced nanoparticles are developed to combine diagnostic imaging and therapy (i.e., theranostics). However, these methods are mostly at an early stage of development. More advanced studies on experimental animals and clinical trials would be needed to introduce some of these techniques to routine clinical practice.Uveal melanoma is the most common intraocular malignancy and arises from melanocytes in the choroid, ciliary body, or iris. The current eye-sparing treatment options include surgical treatment, plaque brachytherapy, proton beam radiotherapy, stereotactic photon radiotherapy, or photodynamic therapy. However, the efficacy of these methods is still unsatisfactory. This article reviews several possible new treatment options and their potential advantages in treating localized uveal melanoma. These methods may be based on the physical destruction of the cancerous cells by applying ultrasounds. Two examples of such an approach are High-Intensity Focused Ultrasound (HIFU)—a promising technology of thermal destruction of solid tumors located deep under the skin and sonodynamic therapy (SDT) that induces reactive oxygen species. Another approach may be based on improving the penetration of anti-cancer agents into UM cells. The most promising technologies from this group are based on enhancing drug delivery by applying electric current. One such approach is called transcorneal iontophoresis and has already been shown to increase the local concentration of several different therapeutics. Another technique, electrically enhanced chemotherapy, may promote drug delivery from the intercellular space to cells. Finally, new advanced nanoparticles are developed to combine diagnostic imaging and therapy (i.e., theranostics). However, these methods are mostly at an early stage of development. More advanced and targeted preclinical studies and clinical trials would be needed to introduce some of these techniques to routine clinical practice.

Ophthalmic Drug Delivery Using Iontophoresis: Recent Clinical Applications.

Background: Iontophoresis is a noninvasive delivery system designed to overcome barriers to ocular penetration of topical ophthalmic medications by employing a low-amplitude electrical current to promote the migration of a charged drug substance across biological membranes. Trans-scleral iontophoresis of dexamethasone phosphate has demonstrated dramatically increased intraocular concentrations of dexamethasone in rabbit ocular tissues compared with topical instillation, including 50- to 100-fold greater aqueous humor concentrations. Methods: This article reviews available data on recent clinical applications of iontophoretic ophthalmic drug delivery. Results: The EyeGate II delivery system (EGDS) is a trans-scleral iontophoresis system that has been used in conjunction with EGP-437, a proprietary-charged formulation of dexamethasone phosphate for iontophoretic delivery. In patients with noninfectious anterior uveitis, EGP-437, delivered through 2 iontophoretic treatments using the EGDS, demonstrated similar efficacy to topical prednisolone acetate 1% eye drops instilled 8 times daily over 28 days, suggesting the potential to decrease or eliminate the need for daily dosing of topical steroids in this patient population. Other applications for EGP-437 delivered through the EGDS that have been explored in clinical trials include treatment of dry eye, postsurgical inflammation and pain, and scleritis. In addition, transcorneal iontophoresis has been used outside of the United States to enhance riboflavin penetration in patients undergoing corneal cross-linking as therapy for progressive keratoconus. Conclusions: The reviewed studies demonstrate the feasibility of using iontophoresis to enhance drug delivery to ocular tissues and support the potential of this noninvasive technique across a range of ophthalmic indications.

Transcorneal iontophoresis of dendrimers: PAMAM corneal penetration and dexamethasone delivery

Iontophoresis of nanocarriers in the eye has been proposed to sustain drug delivery and maintain therapeutic concentrations. Fourth generation polyamidoamine (PAMAM) dendrimers are semi-rigid nanoparticles with surface groups that are easily modified. These dendrimers are known to modulate tight junctions, increase paracellular transport of small molecules and be translocated across epithelial barriers, exhibiting high uptake by different cell lines. The first aim of this study was to investigate the effect of iontophoresis on PAMAM penetration and distribution into the cornea. The second aim was to evaluate, ex vivo and in vivo, the effect of these dendrimers in dexamethasone (Dex) transcorneal iontophoresis. Anionic (PAMAM G3.5) and cationic (PAMAM G4) dendrimers were labeled with fluorescein isothiocyanate (FITC), and their distribution in the cornea was investigated using confocal microscopy after ex vivo anodal and cathodal iontophoresis for various application times. The particle size distribution and zeta potential of the dendrimers in an isosmotic solution were determined using dynamic light scattering and Nanoparticle Tracking Analysis (NTA), where the movement of small particles and the formation of large aggregates, from 5 to 100nm, could be observed. Transcorneal iontophoresis increased the intensity and depth of PAMAM-FITC fluorescence in the cornea, suggesting improved transport of the dendrimers across the epithelium toward the stroma. PAMAM complexes with Dex were characterized by 13C-NMR, 1H-NMR and DOSY. PAMAM G3.5 and PAMAM G4 increased the aqueous solubility of Dex by 10.3 and 3.9-fold, respectively; however, the particle size distribution and zeta potential remained unchanged. PAMAM G3.5 decreased the Dex diffusion coefficient 48-fold compared with PAMAM G4. The ex vivo studies showed that iontophoresis increased the amount of Dex that penetrated into the cornea by 2.9, 5.6 and 3.0-fold for Dex, Dex-PAMAM G4 and Dex-PAMAM G3.5, respectively. In vivo experiments, however, revealed that iontophoresis of Dex-PAMAM-G3.5 increased Dex concentration in the aqueous humor by 6.6-fold, while iontophoresis of Dex-PAMAM G4 and Dex increased it 2.5 and 2-fold, respectively. Therefore, iontophoresis targeted PAMAM to the cornea but it is the sustained delivery of the Dex from PAMAM that prevents its rapid elimination from the aqueous humor. In conclusion, iontophoresis of PAMAM complexes represents a promising strategy for targeted and sustained topical drug delivery to the eye.

Iontophoresis in ophthalmology: A review of the literature

Drug delivery to the inner part of the eye is still a problem in treatment of ocular disease. Iontophoresis has been used in the field of medicine for many years. This technique consists of applying a weak electrical current to drive charged drug molecules across tissue barriers. Transcorneal iontophoresis delivers a high concentration of drug to the anterior segment of the eye (cornea, aqueous humor, ciliary body, iris, and lens), for the treatment of anterior segment diseases. There are different types of iontophoresis such as ophthalmic, transdermal, transungual, oral, buccal, and transnasal. The benefit of iontophoretic drug delivery in ophthalmology lays in its capacity to provide high drug tissue concentration safely, while minimizing the systemic drug exposure. This review summarizes basics of ocular iontophoresis and iontophoretic device, trans corneal and transscleral iontophoresis, and the applications of iontophoresis in ophthalmology.

Advances in Ocular Iontophoresis Research

Ocular iontophoresis is a time tested non-invasive tool for efficient delivery of drugs to both anterior and posterior segments of the eye. The review focuses on history of ocular iontophoresis, recent research developments on transcorneal/transscleral iontophoresis, prominent patents issued and filed on novel iontophoresis devices along with their treatment regimens. The review provides detailed information on development of ophthalmic iontophoretic devices, mode of action and the potential therapeutic applications. Further, the review discusses important clinical trials completed or inprogress on ocular iontophoresis targeting complex ocular disease states. A literary review of important developments in ophthalmic iontophoresis is expected to explore the growing prominence of this technique to effectively deliver drugs to both the superficial and inner ocular compartments targeting complex disease states as Glaucoma and Age Related Macular Degeneration. Keywords: Clinical trials, EyeGate® II Delivery System®, Patents in ocular iontophoresis, Ocuphor® delivery system, targeted iontophorectic drug delivery, Transscleral iontophoresis, transcorneal iontophoresis, Visulex® delivery system

Changes to Euchromatin on LAT and ICP4 Following Reactivation Are More Prevalent in an Efficiently Reactivating Strain of HSV-1

BackgroundEpigenetic mechanisms, via post-translational histone modifications, have roles in the establishment and maintenance of latency of the HSV-1 genome in the sensory neurons. Considering that many post-translational histone marks are reversible in nature, epigenetic mechanisms may also play a critical role in the process of induced HSV-1 reactivation.Methodology/Principal FindingsThis study utilized the rabbit ocular model of HSV-1 infection and reactivation, induced by the transcorneal iontophoresis of epinephrine (TCIE), to characterize changes to chromatin that occur between 0.5 and 4 h following the application of the reactivation stimulus. Our goal was to explore the hypothesis that chromatin remodeling is an early and essential step in the process of HSV-1 reactivation. Analysis of the HSV-1 latently infected rabbit trigeminal ganglia (TG) showed that enrichment of the euchromatic marker H3K4me2 significantly decreased in the LAT 5′exon region (∼2.5-fold) and significantly increased in the lytic ICP4 promoter region (∼3-fold) by 1 h post-TCIE in the highly efficient reactivating McKrae strain of HSV-1. In contrast, we observed no significant change in the euchromatic marks of H3K4me2 associated with LAT 5′exon or ICP4 promoter regions of the poorly reactivating KOS strain of HSV-1 following TCIE through 4 h. The implication that these observed epigenetic changes were linked to transcriptional activity was confirmed by qRT-PCR examining both LAT and lytic transcript abundance following TCIE. We found a significant decrease in the abundance of LAT RNA by 2 h post-iontophoresis of epinephrine coupled to an increase in the transcript abundance of ICP4 in the McKrae strain of HSV-1. By comparison, we observed no change in the LAT or ICP4 transcript abundance of the poor reactivator KOS following iontophoresis of epinephrine through 4 h.Conclusions/SignificanceOur results implicate that chromatin remodeling is an early and essential step involved in the process of in vivo HSV-1 reactivation.

Transcorneal Iontophoresis for Delivery of Ciprofloxacin Hydrochloride

Purpose: To investigate the feasibility of utilizing iontophoresis for delivery of ciprofloxacin hydrochloride to the anterior chamber of the eye and to carry out systematic studies to investigate the effect of electrical protocol on the transcorneal drug delivery. Materials and Methods: Effect of current density (0.75 mA/cm2 to 6.25 mA/cm2 applied for 5 minutes) on drug permeation across the cornea and drug load in the cornea were investigated in vitro as well as ex vivo studies in porcine cornea model. Tolerability studies were carried out in rabbits. Cytotoxicity studies were conducted in cultured corneal tissue. Results: The drug loaded in the cornea increased with increasing current density. After 5 minutes of iontophoresis, the drug concentration in the receiver compartment fluid (in vitro) or in aqueous humor (ex vivo) was not significantly higher than control (in which electric current was not applied). However, waiting for 6–12 hours after iontophoresis for 5 minutes, the concentrations of drug in aqueous humor in ex vivo studies were ∼6 and ∼5-fold higher than control (130.12 ± 78.99 ng/ml), respectively. Cytotoxicity studies demonstrated the safety of the technique. The application of 6.25 mA/cm2 for 5 minutes (right eye) did not show any sign of loss of vision and abnormal discharge, redness of eye, or edema when compared to the control left eye. Conclusions: Transcorneal iontophoresis is a potential method of delivering effective levels of ciprofloxacin hydrochloride into aqueous humor for the treatment of intraocular infections. This study unveils the ability of iontophoresis to rapidly drive ciprofloxacin into the cornea where a drug reservoir is formed, which eventually releases slowly into aqueous humor, eliciting sustained therapeutic effect.

Transcorneal and transscleral iontophoresis of dexamethasone phosphate using drug loaded hydrogel

Purpose To evaluate dexamethasone penetration to the eye after a short transcorneal and transscleral iontophoresis using a drug loaded hydrogel assembled on a portable iontophoretic device. Methods Iontophoresis of dexamethasone phosphate was studied in healthy rabbits using drug loaded disposable HEMA hydrogel sponges and portable iontophoretic device. Corneal iontophoretic administration was performed with a current intensity of 1 mA for 1 and 4 min. Transconjunctival and transscleral iontophoresis were performed twice for 2 min at two near places in the pars-plana area, on the conjunctival membrane or directly on the sclera. Dexamethasone concentrations were assayed using HPLC. Results Dexamethasone levels in the rabbit cornea after a single transcorneal iontophoresis for 1 min were up to 30 fold higher compared to those obtained after frequent eye drop instillation. Also, high drug concentrations were obtained in the retina and sclera 4 h after transscleral iontophoresis. Conclusions A short low current non-invasive iontophoretic treatment using dexamethasone-loaded hydrogels has potential clinical value in increasing drug penetration to the anterior and posterior segments of the eye.

Overlapping subdeletions within a 348-bp in the 5′ exon of the LAT region that facilitates epinephrine-induced reactivation of HSV-1 in the rabbit ocular model do not further define a functional element

A previous study identified a 348-bp region at the 5′ end of the 8.5-kb latency-associated transcript (LAT) of HSV-1 strain 17Syn+ that is necessary for maximum adrenergically induced reactivation following transcorneal iontophoresis of epinephrine (D.C. Bloom et al., 1996, J. Virol. 70, 2449–2459). In that study, the construct with complete deletion of the 348-bp region, 17Δ348, failed to achieve the high reactivation frequency demonstrated by the parent (17Syn+) and rescued (17Δ348R) viruses. To further characterize the function of the 348-bp region, we analyzed two genetic constructs with partial deletions in the same 348-bp region, 17Δ201 and 17Δ207, in the rabbit model. Both constructs exhibited the same high reactivation frequencies demonstrated by the parent 17Syn+ and the rescued 17Δ348R viruses. These results suggest that the control of reactivation is distributed over a large portion of the 348-bp region, rather than being confined within a smaller, more discrete region. To assess whether the low reactivation phenotype of the 17Δ348 construct was caused by a requirement for proper spacing of elements outside the 348-bp region, we constructed a virus (17Δ348St) that contained a 360-bp stuffer fragment of heterologous DNA ( lacZ) to maintain the proper spacing. The 17Δ348St construct also displayed a low reactivation phenotype, similar to that of 17Δ348, suggesting that the effect of deleting this segment of the 5′ exon of LAT is obtained through a mechanism other than the disruption of spacing.

Changes in gene expression in latent HSV-1-infected rabbit trigeminal ganglia following epinephrine iontophoresis

Purpose. The aim of the present study was to identify the genes that express in the nervous system when herpes simplex virus type 1 (HSV-1) reactivates from latency by using subtraction cloning following epinephrine iontophoresis. Methods. The corneas of New Zealand White rabbits (2 to 2.5 kg) were topically inoculated with 5 × 10 5 PFU of plaquepurified HSV-1 strain McKrae. Corneal infection was monitored by slit lamp examination (SLE) on days 3-7 after infection. At 30d post-infection, eyes were assessed for infectious virus by ocular swabs. Disappearance of virus in ocular swabs signified latency for HSV-1. Latently-infected rabbits were subjected to transcorneal iontophoresis. The messenger RNA (mRNA) was isolated from the trigeminal ganglia and used for subtraction cloning and subtraction library synthesis. Results. Our results indicate 18 genes with increased expression and 6 genes with decreased levels. Northern blot analysis revealed that genes for OX-40 ligand, MHC class II HLA-DR-a and ß-microglobulin showed predominant increase followed by tyrosine 3'-monooxygenase, proteolipid protein, tyrosine beta, and apolipoprotein D. Genes that underwent reduced expression included cytochrome c oxidase subunit I, ATP synthase isoform, cytochrome b, ATPase 9, and at least one unidentified gene. Conclusions. Our results, particularly the increased detection of OX-40 ligand and MHC class II-a and ß-2 microglobulin, support the finding that lymphocytes persist in latentlyinfected trigeminal ganglia (TGs). These results also suggest a role of the immune system in HSV-1 recurrences. In addition, we have detected genes associated with neuronal disorders, OX-40L, proteolipid protein, and apolipoprotein D.

Reactivation and donor-host transmission of herpes simplex virus after corneal transplantation.

To review our previous studies regarding herpes simplex virus type 1 (HSV-1) corneal latency in the rabbit lamellar keratoplasty (LK) and penetrating keratoplasty (PKP) models. Rabbits latently infected with HSV- I received allografts from naive rabbits, and naive rabbits received grafts from rabbits latently infected with HSV-1. In rabbits undergoing LK, viral shedding in tear film and the occurrence of herpetic lesions were investigated for 7 days after operation. In rabbits undergoing PKP, latency-associated transcript (LAT)-positive and -negative HSV- I mutants were used to establish latency. Ninety days after PKP, reactivation of HSV-1 was induced by transcorneal iontophoresis of epinephrine. Viral shedding was then assessed by tear-film swabbing. Donor corneal buttons, recipient corneal rims, and corresponding trigeminal ganglia were analyzed for HSV DNA concentration and viral transcription. In rabbits undergoing LK, the occurrence of positive tear-film cultures and number of days on which corneal epithelial lesions were observed were significantly higher in the operated eyes of latently infected rabbits as compared with controls. In rabbits undergoing PKP, HSV- I could transmit between host and donor tissues both in anterograde and retrograde fashion. LAT-positive virus had a significantly greater ability to transmit. Higher concentrations of HSV DNA detected in cornea and trigeminal ganglia correlated with active viral transcription and higher percentage of viral shedding. Corneas from latently infected rabbits contain HSV-1 DNA that can replicate and transmit after induced reactivation. Our studies provide further evidence for corneal latency of this virus.

A 437-base-pair deletion at the beginning of the latency-associated transcript promoter significantly reduced adrenergically induced herpes simplex virus type 1 ocular reactivation in latently infected rabbits.

In this study we used a herpes simplex virus type 1 (HSV-1) deletion mutant to identify a segment of the genome necessary for epinephrine-induced reactivation in the rabbit eye model of herpetic recurrent disease. In HSV-1 latently infected neural tissue, the only abundant viral products are the latency-associated transcripts (LATs). At least one promoter of LAT has been identified, and mutations in the LAT domain have been used to investigate HSV-1 reactivation. We used an ocular rabbit model of epinephrine-induced HSV-1 reactivation to study the effects of deleting a 437-bp region beginning 796 bp upstream of the LAT CAP site. Specifically, the 437-bp deletion is located between genomic positions 118006 and 118443 of the parent 17Syn+, and the construct is designated 17 delta S/N. This region also controls a portion of the genome encoding two transcripts (1.1 and 1.8 kb) from the LAT domain. A rescuant, 17 delta S/N-Res, was constructed from 17 delta S/N. Following ocular infection, all three viruses produced similar acute dendritic lesions in rabbits. Five weeks after infection, rabbits received transcorneal iontophoresis of epinephrine. The parent, 17Syn+, and the rescuant, 17 delta S/N-Res, underwent a high frequency of HSV-1 ocular reactivation as determined by recovery of infectious virus in the tear film. Rabbits infected with 17 delta S/N had a significantly lower frequency of ocular reactivation. Analysis of the trigeminal ganglia from all three groups of latently infected rabbits revealed (i) similar amounts of HSV DNA (genomic equivalents), (ii) accumulation of 2.0- and 1.45-kb LATs, and (iii) explant reactivation at the same high frequency. Therefore, these studies indicate that the 437-bp deleted region in 17 delta S/N is essential for epinephrine-induced reactivation and could implicate the 1.1- and 1.8-kb transcripts in the mechanisms controlling HSV-1 reactivation.

In vivo epinephrine reactivation of ocular herpes simplex virus type 1 in the rabbit is correlated to a 370-base-pair region located between the promoter and the 5' end of the 2.0 kilobase latency-associated transcript.

A rabbit ocular model of epinephrine-induced herpes simplex virus type 1 reactivation was employed to study the effect of a deletion in the latency-associated transcript domain. A viral construct derived from 17Syn+, designated 17deltaSty, has a deletion of 370 nucleotides between genomic positions 118880 and 119250. 17deltaSty has been shown to reactivate with wild-type virus kinetics from explants of trigeminal ganglia from latently infected mice. To determine the behavior of this mutant in an in vivo, inducible reactivation system, rabbit corneas were infected with 17Syn+, 17deltaSty, or its rescuant, 17detlaSty-Res. After viral latency was established, transcorneal epinephrine iontophoresis was performed. The rabbits latently infected with 17deltaSty exhibited a significantly reduced ability to undergo adrenergically induced reactivation, i.e., viral shedding in the tears, compared with rabbits infected with either 17Syn+ or 17deltaSty-Res. However, quantitative PCR demonstrated similar numbers of viral genomes in the trigeminal ganglia from rabbits latently infected with all three viruses, and all three viruses reactivated in vitro with wild-type kinetics in an explant cocultivation assay. These studies indicate that the 370-bp region deleted in the 17deltaSty construct plays a role in epinephrine-induced reactivation.

Pharmacokinetic considerations in the treatment of bacterial keratitis.

The eye is relatively impermeable to micro-organisms and other environmental elements. However, if corneal integrity is breached by trauma, a sight-threatening bacterial infection can result. Staphylococcus aureus, Pseudomonas aeruginosa, and Streptococcus pneumoniae are the most common bacterial pathogens associated with infection of compromised corneas. Bacterial enzymes and toxins, as well as factors associated with the host immune response, can lead to tissue destruction during corneal infection. For successful therapy, an antibacterial agent must be active against the pathogen and must be able to overcome the permeability barrier of the cornea. Topical application of antibacterial agents adequately delivers drugs to the cornea and aqueous humour. However, drug concentrations at the site of infection are not always sufficient to rapidly kill infective organisms. Infections with antibiotic-resistant strains present an even greater therapeutic challenge. In addition, sterilisation of the cornea by antibacterial agents does not eliminate inflammation and corneal scarring that accompany infection. Steroidal and non-steroidal antiinflammatory agents limit corneal scarring during experimentally induced bacterial keratitis. However, although promising, concomitant use of these drugs with antibacterial agents remains controversial. Two ocular drug delivery systems that provide high and sustained concentrations of drug to ocular tissues are corneal collagen shields and transcorneal iontophoresis. The collagen shield, originally designed as a bandage lens, prolongs drug contact with the cornea. Chemotherapeutic studies of experimental bacterial keratitis demonstrate that shields hydrated with antibacterial agents reduce bacteria in the cornea as well as or better than frequent applications of fortified antibacterial drops. Transcorneal iontophoresis uses an electric current to drive charged drugs into the cornea. In experimentally induced bacterial keratitis, transcorneal iontophoresis of antibacterial agents is superior to topically administered ocular drops for reducing the numbers of bacteria in the cornea. Although both drug delivery systems appear to be well tolerated and nontoxic in animal models, clinical trials in patients are required to determine the usefulness of these drug delivery systems in clinical trials. Based on present experimental results, future therapy of bacterial keratitis will involve efficient drug delivery devices, the use of new antibacterial agents or combinations of presently available antibacterial agents, and careful use of adjuvant anti-inflammatory agents.

Experimental myopia in a diurnal mammal (Sciurus carolinensis) with no accommodative ability.

1. We examined the functional morphology of the intra-ocular muscles of the grey squirrel using pharmacological and histological methods. Using sympathomimetic (phenylephrine) and parasympathomimetic (carbachol) agents, administered by transcorneal iontophoresis, the response of the iris sphincter and dilator muscles and the ciliary muscle were recorded. Measurement techniques included both streak retinoscopy and coincidence optometry for measurement of ocular refraction and high resolution ultrasonography to monitor changes in the intra-ocular component dimensions. 2. The grey squirrel was found not to possess a functional accommodative system. No change in ocular refraction or intra-ocular dimensions could be induced with 40% carbachol. Marked changes in pupil diameter occurred with topical application of both phenylephrine (dilation) and carbachol (constriction). Histological findings were in agreement with pharmacological findings in showing well developed iris sphincter and dilator muscles but only a poorly developed ciliary muscle. 3. Calculation of the depth of focus of the grey squirrel eye reveals that this could be sufficient to account for the behavioural observations of near viewing habits. 4. We then determined whether we could induce axial elongation of the vitreous chamber and a consequent myopia by monocular deprivation (MD) of pattern vision. 5. Monocular deprivation of pattern vision produced a significant experimental myopia due to axial elongation of the vitreous chamber in the deprived eye. 6. The results demonstrate that a functional accommodative system is not necessary to induce experimental myopia in the grey squirrel eye.

Device Drug Delivery to the Eye: Collagen Shield's, Iontophoresis, and Pumps

AbstractExternal devices have been used to enhance drug delivery. This article reviews the role of collagen shields, iontophoresis, and pumps used to deliver ophthalmic medications. Collagen shields have been used to deliver drugs and promote corneal epithelial healing. Presoaked collagen shields deliver many drugs to the eye as well as or better than traditional methods such as frequent topical therapy or subconjunctival injection. The efficacy of drug delivery by collagen shields was demonstrated in animal models of graft rejection and bacterial keratitis. lontophoresis uses an electrical current to carry an ionized drug across tissue. Transcorneal iontophoresis delivers high concentrations of a drug to the anterior segment of the eye. Transscleral iontophoresis bypasses the lens-iris diaphragm and produces adequate vitreous levels. Pumps deliver fluid to the eye for extended periods of time via a tube with its distal opening in the conjunctival sac, corneal stroma, anterior chamber, or vitreous cavity. Clinical acceptance of the collagen shield for drug delivery to the anterior segment is better than iontophoresis or pumps, probably because the collagen shield is simpler and more convenient to use.

Transscleral and Transcorneal lontophoresis of Ketoconazole in the Rabbit Eye

The authors assessed the efficacy of transscleral and transcorneal iontophoresis of ketoconazole as a method of drug delivery to the aqueous humor, vitreous, and cornea of the rabbit eye. Transscleral iontophoresis (4–6 mAmps for 15 minutes) achieved peak ketoconazole concentrations in the aqueous 1 hour after treatment (10.2 μg/ml) and remained at fungicidal therapeutic concentrations for 8 hours; in the vitreous, a peak concentration of 0.1 μg/ml occurred between 1 and 2 hours posttreatment. Transcorneal iontophoresis (1.5 mAmps for 15 minutes) achieved peak corneal concentrations of 27.6 μg/ml and peak aqueous concentrations of 1.4 μg/ml, both 1 hour after Iontophoresis. Fungicidal therapeutic drug concentrations were sustained for 2 hours both in the cornea and in the aqueous. These concentrations were compared with those obtained after subconjunctival injection (peak values): 0.8 μg/ml in aqueous, 5.9 μg/ml in cornea, and 0.7 μg/ml in vitreous, all within 1 hour of injection. Aqueous and corneal concentrations were significantly higher after transscleral and transcorneal iontophoresis than subconjunctival injection (P < 0.05). Iontophoresis is proposed as an effective means of delivering high concentrations of ketoconazole to the anterior segment of the eye.

Transscleral and transcorneal iontophoresis of vancomycin in rabbit eyes.

We examined the ability of transscleral and transcorneal iontophoresis to deliver vancomycin into the aqueous humor, the vitreous humor, and the cornea of rabbit eyes. Control eyes receiving subconjunctival injection (25 mg) attained peak aqueous, vitreous, and corneal concentrations (mean +/- S.E.M.) of 14.73 +/- 0.35 mcg/ml (at 4 hours after injection), 1.10 +/- 0.78 mcg/ml (2 hours), and 1167 +/- 63 mcg/g (1 hour), respectively. Eyes receiving transscleral iontophoresis (3.5 mA for 10 minutes) attained significantly higher vitreal levels than controls: 6.33 +/- 0.25 mcg/ml (p less than 0.001; 1 hour), 13.43 +/- 2.32 mcg/ml (p less than 0.01; 2 hours), 11.93 +/- 0.76 mcg/ml (p less than 0.001; 4 hours), 8.40 +/- 0.60 mcg/ml (p less than 0.001; 8 hours). Eyes receiving transcorneal iontophoresis (0.5 mA for 5 minutes) attained earlier and significantly higher aqueous and corneal levels than controls. Aqueous humor levels were 16.20 +/- 3.19 mcg/ml (p less than 0.05; 1 hour) and 20.20 +/- 0.43 mcg/ml (p less than 0.001; 2 hours). Corneal levels were 10799 +/- 755 mcg/g (p less than 0.001; 0.5 hour), 4856 +/- 606 mcg/g (p less than 0.005; 1.0 hour), 2185 +/- 71 mcg/g (p less than 0.001; 2 hours), and 710 +/- 112 mcg/g (p less than 0.025; 4 hours). Corneal endothelial cell counts were decreased by 8.8% (p = 0.08) after transcorneal iontophoresis of vancomycin and 5.4% (p less than 0.02) following Balanced Salt Solution (BSS). However, corneal thickness were not significantly increased by iontophoresis of either vancomycin or BSS. These experiments show that transscleral and transcorneal iontophoresis are efficacious in delivering high concentrations of vancomycin into the aqueous and vitreous humor and the cornea.

Responses of iris blood flow to stimulation of the cervical sympathetic in the rabbit

o (1) The effects of α- and β-blocking agents (phentolamine and propranolol) on the responses of iris vessels to stimulation of the cervical sympathetic in albino rabbits were studied. Vascular responses were expressed in terms of percentage changes of vascular heat dissipation ( Cole and Rumble, 1970 ). (2) Using square wave stimulation at 21 Hz there was a linear relationship of vascular response to stimulus intensity and the action of the antagonists was shown by alterations in the slope of the stimulus/response line. (3) Phentolamine given by close arterial infusion, intravitreal injection or transcorneal iontophoresis markedly diminished the response to sympathetic stimulation but propranolol had little or no effect. In further experiments the log dose response curves to exogenous noradrenaline and isoprenaline showed the action of noradrenaline to be enhanced 24 hr after superior cervical ganglionectomy whilst the isoprenaline response was unchanged. (4) The experiments with blocking agents suggested the β-receptor sites subserved little or no part in the response to sympathetic stimulation. The ganglionectomy experiments indicate that sites in the iris responsible for isoprenaline uptake are either absent or extraneuronal.