Ocular delivery of acetylsalicylic acid by repetitive coulomb-controlled iontophoresis

To investigate the potential of transscleral coulomb-controlled iontophoresis (CCI) for repetitive delivery of acetylsalicylic acid (ASA) into the eye, a total of 50 rabbits was included in this study. Fourteen animals received serial CCI treatment. Fourteen animals underwent CCI with either ASA or balanced salt solution (BSS) for at least 6 days at 24- and 48-hour intervals. Eighteen animals received a single CCI application, while 18 animals were injected with 15 mg ASA/kg body weight intravenously. HPLC analysis was performed to determine the levels of salicylic acid (SA) in ocular tissues. Apart from clinical follow-up, 2 rabbits in the ASA and BSS groups were examined by electroretinography, and 2 animals were examined histologically. Though high concentrations of SA were measured, no alterations were observed clinically, histologically and electrophysiologically. Repetitive CCI demonstrated its potential as a topical drug delivery system for ASA into the eye. This transscleral delivery of ASA resulted in significant and sustained intraocular concentrations of SA without side effects. Iontophoresis may be advantageous in clinical administration maintaining therapeutic levels of ASA while avoiding adverse effects associated with the systemic administration of nonsteroidal anti-inflammatory drugs.     

Methotrexate delivery to the eye using transscleral hydrogel iontophoresis

PURPOSE: To evaluate methotrexate penetration and distribution profile in ocular structures after short low current transscleral hydrogel iontophoresis. METHODS: Methotrexate iontophoresis was studied in rabbits using drug-loaded hydrogels mounted on a portable iontophoretic device. Drug distribution profile was evaluated 2, 4, and 8 hours after iontophoretic treatment of 1.6 mA/cm2 for 4 min. Ocular drug levels were also determined two hours after iontophoretic treatment of 5 mA/cm2, compared to mock iontophoresis and intravitreal injection of methotrexate. RESULTS: Therapeutic drug levels were maintained for at least 8 h at the sclera and retina and for 2 h at the aqueous humor following the iontophoretic treatment. After increasing the current density, a twice-higher concentration was achieved at the vitreous and 8 to 20 time higher concentrations at the retina and sclera. CONCLUSIONS: A short low current non-invasive iontophoretic treatment using methotrexate-loaded hydrogels has a potential clinical value in treating ocular inflammatory diseases and intraocular lymphoma.     

Transcorneal Extrusion of an Intraocular Lens

An 82-year-old woman was treated for pseukophakic bullous keratopathy with a penetrating keratoplasty complicated by a postoperative retinal detachment. The retina was reattached successfully but impaired visual acuity remained. She was lost to follow-up for 14 months. Upon re-examination the pseudophakic lens optic had eroded completely through the donor cornea. Histologic study of the enucleated eye suggests that the intraocular lens optic came in contact with the posterior cornea after a transient wound dehiscence. The lens haptics, still attached to the optic, extended through anterior corneal scar tissue into the globe. The globe remained sterile and intact during the extrusion process. This case emphasizes the importance of selecting patients who will comply with postoperative care and the need to minimize contact between intraocular lenses and ocular tissue.     

Methylprednisolone delivery to the back of the eye using hydrogel iontophoresis.

AIM: The aim of this study was to evaluate methylprednisolone penetration into ocular structures after low-current trans-scleral hydrogel iontophoresis, as compared with the common intravenous (i.v.) treatment. METHODS: Methylprednisolone hemisuccinate (MPH) iontophoresis was studied in rabbits, using drug-loaded hydrogels mounted on a portable iontophoretic device. Cathodal iontophoresis of 2.6 mA/cm(2) was applied for 5 min at two opposite sites on the sclera or for 10 min at the same site. Ocular drug levels were determined 2 h after iontophoretic treatment, then compared to mock iontophoresis and i.v. infusion of 10 mg/kg methylprednisolone. RESULTS: Significantly higher methylprednisolone levels were found in ocular tissues after iontophoresis, compared with the control groups, except for the sclera concentrations, which were similar to the concentrations achieved after mock iontophoresis. Two (2) h after the trans-scleral iontophoretic treatment, 178.59 +/- 21.63 microg/g, 6.74 +/- 2.38 microg/ml, and 2.71 +/- 0.57 microg/mL were found in the retina, aqueous humor, and vitreous, respectively. No significant differences were found between one or two site treatments of trans-scleral iontophoresis. Nondetectable concentrations were found 2 h after the i.v. infusion of 10 mg/kg of methylprednisolone in all evaluated ocular tissues and fluids. CONCLUSIONS: A short, low-current noninvasive iontophoretic treatment, using methylprednisolone-loaded hydrogels, has potential clinical value in treating ocular inflammatory diseases.     

Reversible visual loss in a patient receiving high-dose ciprofloxacin hydrochloride (Cipro)

Bilateral acute visual loss characterized by cecocentral scotomas and acquired dyschromatopsia developed in a patient receiving large oral doses of ciprofloxacin hydrochloride (Cipro). The visual defects improved after cessation of this antibiotic. To our knowledge, this association has not been described previously. The use of this medication in high doses must be accompanied by careful monitoring of optic nerve function.     

Transcorneal oxygen therapy for glaucoma associated with sickle cell hyphema

PURPOSE: To study three patients with glaucoma caused by sickle cell hyphema who were successfully treated with transcorneal oxygen therapy. METHODS: Case reports. Three patients with increased intraocular pressure caused by sickle cell hyphema were administered transcorneal oxygen therapy using humidified oxygen at a flow rate that ranged from 1 to 3 l/minute. RESULTS: All three patients had a dramatic reduction in their intraocular pressure within hours of receiving oxygen therapy. No complications were associated with the oxygen therapy. CONCLUSION: Transcorneal oxygen therapy can reduce intraocular pressure in patients with glaucoma from sickle cell hyphema. Further study is warranted to evaluate this new therapy.     

Transcorneal electrical stimulation shows neuroprotective effects in retinas of light-exposed rats

Purpose. To examine the effects of transcorneal electrical stimulation (TES) on retinal degeneration of light-exposed rats. Methods. Thirty-three Sprague Dawley albino rats were divided into three groups: STIM (n = 15) received 60 minutes of TES, whereas SHAM (n = 15) received identical sham stimulation 2 hours before exposure to bright light with 16,000 lux; healthy animals (n = 3) served as controls for histology. At baseline and weekly for 3 consecutive weeks, dark- and light-adapted electroretinography was used to assess retinal function. Analysis of the response versus luminance function retrieved the parameters Vmax (saturation amplitude) and k (luminance to reach ½Vmax). Retinal morphology was assessed by histology (hematoxylin-eosin [HE] staining; TUNEL assay) and immunohistochemistry (rhodopsin staining). Results. Vmax was higher in the STIM group compared with SHAM 1 week after light damage (mean intra-individual difference between groups 116.06 μV; P = 0.046). The b-wave implicit time for the rod response (0.01 cd.s/m(2)) was lower in the STIM group compared with the SHAM group 2 weeks after light damage (mean intra-individual difference between groups 5.78 ms; P = 0.023); no other significant differences were found. Histological analyses showed photoreceptor cell death (TUNEL and HE) in SHAM, most pronounced in the superior hemiretina. STIM showed complete outer nuclear layer thickness preservation, reduced photoreceptor cell death, and preserved outer segment length compared with SHAM (HE and rhodopsin). Conclusions. This sham-controlled study shows that TES can protect retinal cells against mild light-induced degeneration in Sprague Dawley rats. These findings could help to establish TES as a treatment in human forms of retinal degenerative disease.     

Device drug delivery to the eye. Collagen shields, iontophoresis, and pumps

External 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. Iontophoresis 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.     

Ciprofloxacin iontophoresis for aminoglycoside-resistant pseudomonal keratitis

Studies using ciprofloxacin for the therapy of experimental aminoglycoside-resistant keratitis caused by Pseudomonas aeruginosa were conducted using transcorneal iontophoresis as the drug-delivery system. Corneas infected with P. aeruginosa ATCC 27853/pMG6 were treated 22 hours postinfection with ciprofloxacin delivered by iontophoresis (0.8 mA X 10 min), mock iontophoresis (eyecup with no current), or frequently applied topical drops. Iontophoresis of 10 mg/ml or 25 mg/ml of ciprofloxacin significantly reduced the number of viable bacteria per cornea by more than 5 log units compared with untreated controls (P less than 0.0001). Five hours after the initiation of treatment, mock iontophoresis (10 mg/ml or 25 mg/ml) or 11 applications of topical ciproflaxicin drops (7.5 mg/ml) decreased the viable bacteria relative to the untreated controls by 5 log units (P less than 0.0001). One treatment with an eyecup was as effective as 11 treatments with topical drops (P greater than 0.75). One hour after treatment with iontophoresis or mock iontophoresis of 10 mg/ml of ciprofloxacin, aqueous humor concentrations were 83.75 +/- 8.85 micrograms/ml and 24.87 +/- 4.0 micrograms/ml (mean +/- standard error of the mean), respectively. One hour after the last of five applications of 7.5 mg/ml of ciprofloxacin (every 15 min for 1 hr) the aqueous humor concentration was 4.2 +/- 1.14 micrograms/ml. These results show the value of ciprofloxacin in treating aminoglycoside-resistant infections caused by P. aeruginosa and suggest that ciprofloxacin can be efficiently delivered by iontophoresis.     

Magnetic resonance imaging study of current and ion delivery into the eye during transscleral and transcorneal iontophoresis

PURPOSE: The objectives were to determine by nuclear magnetic resonance imaging (MRI) the target sites of ion delivery in the eye during iontophoresis, compare transscleral and transcorneal ocular iontophoresis, and monitor the distribution of a probe ion in the anterior chamber and vitreous after iontophoretic delivery. METHODS: Thirty-minute 2-mA anodal constant current transscleral and transcorneal iontophoresis (current density, 10 mA/cm(2)) was performed on three New Zealand White rabbits in vivo. Intravitreal injection and passive delivery were the controls. Transscleral and transcorneal iontophoresis experiments were conducted with the electrode device placed in the superior cul-de-sac away from the limbus and on the cornea adjacent to the limbus, respectively. During iontophoresis, the current delivered into the eye was monitored using a probe ion (Mn(2+)) with MRI. The distributions of the ion in the aqueous and vitreous humor after iontophoresis, passive delivery, and intravitreal injection were also determined by MRI. RESULTS: With the short application time, passive diffusion did not deliver a significant amount of the ion into the eye. Whereas transscleral iontophoresis delivered the ion into the vitreous, transcorneal iontophoresis delivered the ion into the anterior chamber. The current pathways during iontophoresis were mainly from the electrode into the eye, perpendicular to the electrode-eye interface beneath the electrode. Electric current along the surface of the globe was relatively minimal. With the present transscleral iontophoresis protocol, the ion penetrated the sclera and traveled as far as 1.5 mm from the electrode-conjunctiva interface into the vitreous. For transcorneal iontophoresis, the ion penetrated the cornea and filled the entire anterior chamber. CONCLUSIONS: MRI can be a useful technique in the study of the penetration of probe compounds in the eye during and after iontophoresis, such as in iontophoresis protocol and device testing. Ocular pharmacokinetic studies using MRI are noninvasive and provide real-time data without perturbation and compound redistribution that can occur during dissection and assay in traditional pharmacokinetic studies. With MRI, it was shown that transscleral iontophoresis, transcorneal iontophoresis, and intravitreal injection deliver ions to different parts of the eye.     

Transcorneal flux of topical pilocarpine to the human aqueous.

Aqueous fluid was withdrawn from eyes of patients undergoing cataract extraction at various intervals after administration of two drops of 2% pilocarpine HCl in a standard manner. Determination of aqueous pilocarpine concentration was made both by spectroscopy of a ferric hydroxylamine complex and by gas-liquid chromatography. Results of both methods were consistent in indicating that concentration does not rise at any time following such topical instillation beyond 5 microgram/ml, with an average of 1.67 microgram/ml, representing a flux efficiency of 0.03%. These findings correlate well with previous investigations of transcorneal flux of pilocarpine for the rabbit in a transport chamber system, in which comparable low flux efficiency was found after simulated drop administration. This serves in some measure to validate an extrapolation of other findings in chamber experiments to the living human eye.     

An improved apparatus for transscleral iontophoresis of gentamicin.

The authors previously found that positively charged substances are less well-transported into the vitreous humor by transscleral iontophoresis than are negatively charged substances. There was more bubble formation in the eye cup with positively charged than with negatively charged substances. The authors hypothesized that these bubbles might account for the poorer conductance of the positively charged species by causing interruptions of the current. Therefore, the authors developed a modified eye cup in which the diameter of the fluid column was larger than that in the old device (1.0 rather than 0.5 mm). This modification allowed larger voltage to be applied than with the older device, because bubbles could be more easily cleared from the conjunctiva than with the narrower-bore eye cup. Although the efficiency of the apparatus was the same with the two eye cups (micrograms per milliliter in vitreous humor divided by milliampere minutes of current applied), vitreal concentrations of gentamicin with the modified eye cup were fourfold higher than with the older eye cup (83 versus 19 micrograms/ml; P < 0.001). These studies suggest that modifying the eye cup to permit easier removal of bubbles resulted in improved delivery of gentamicin into the ocular humors.     

Transcorneal electrical stimulation of retina to treat longstanding retinal artery occlusion

Purpose To report the outcome of transcorneal electrical stimulation (TES) of the visual system on long-standing retinal artery occlusion (RAO). Design Open labeled, case series. Patients and methods Two patients with central RAO (15 and 33 months respectively) and one with branch RAO (26 months) underwent TES therapy. Subjective and objective ophthalmological evaluations were performed before and after the TES. The ages of the patients were 38, 49, and 63 years. The TES (20 Hz biphasic pulses, 30 minutes, up to 1100 uA) was delivered by a bipolar contact lens electrode once a month for 3 months. Perimetric and/or electrophysiological examinations were performed as outcome measures. Results The visual acuity improved by more than 0.2 logMAR units in two cases, and the visual fields were improved in all three cases. The multifocal ERGs which had been reduced in the loci corresponding to the ischemic retinal area were improved after the treatment in two cases. Neither ocular nor systemic adverse effects were observed except for transient superficial keratitis. Conclusions TES of the retina can improve retinal function in eyes with long-standing RAOs. None of the authors have any financial or proprietary interest in any material or methods mentioned. This study was supported by Researches on Sensory and Communicative Disorders from the Ministry of Health, Labor, and Welfare, Japan.     

哌仑西平眼部离子导入治疗近视的药效学研究

目的观察哌仑西平眼部离子导入治疗近视的药效，为哌仑西平的临床使用提供实验依据。方法出生3周的花色豚鼠81只,随机分为9组，其中7组以单眼眼睑缝合法建立形觉剥夺性近视模型。在进行近视诱导的同时,9个组别分别接受如下处理：3组进行形觉剥夺眼的哌仑西平电场促透（离子导入），其中包括高、中、低三种不同的电流强度（PIRx-MD）；1组为形觉剥夺眼的空白对照组高电流强度离子导入（Vehicle0．3-MD）；1组为无电场促透的哌仑西平局部滴眼（PIR-MD）；1组为无电场促透的阿托品局部滴眼（At-ropine-MD）；1组为单纯形觉剥夺对照组（Normal-MD）；其余2组未建立形觉剥夺，作为对照。处理时间30d。检验指标包括屈光度、眼球前后径、眼球重量和组织病理学。结果Normal-MD和Vehicle 0．3-MD组实验眼诱导出-4．64D和-4．33D的近视,哌仑西平离子导入的3组分别诱导出-2．15D、-0．17D、-1．30D的近视；Normal-MD组实验眼的眼球前后径在实验结束时较对照眼增加0．3mm。哌仑西平离子导入的3组分别增加-0.1mm、0mm、-0．1mm：Normal-MD组眼球重量较对照眼增加0．02g,哌仑西平离子导入的3组分别增加0g、0g、-0．02g。两者之间差异均有统计学意义。所有实验眼光镜病理检查未发现异常改变。结论哌仑西平眼部离子导入抑制实验性近视效果明显优于局部滴眼,和阿托品作用类似；同时不引起眼组织的病理改变。     

Iodide iontophoresis as a treatment for dry eye syndrome

BACKGROUND/AIMS: Among the causes related to the development or perpetuation and aggravation of dry eye disease, oxidative reactions may have a role in the pathogenesis of this disorder. Antioxidants, such as iodide, have shown a strong effect in preventing the oxidative damage to constituents of the anterior part of the eye. In this clinical trial the effectiveness of iodide iontophoresis and iodide application without current in moderate to severe dry eye patients was compared. METHODS: 16 patients were treated with iodide iontophoresis and 12 patients with iodide application without current for 10 days. Subjective improvement, frequency of artificial tear application, tear function parameters (break up time, Schirmer test without local anaesthesia), vital staining (fluorescein and rose bengal staining) as well as impression cytology of the bulbar conjunctiva were evaluated before treatment, 1 week, 1 month, and 3 months after treatment. RESULTS: A reduction in subjective symptoms, frequency of artificial tear substitute application, and an improvement in certain tear film and ocular surface factors could be observed in both groups. A stronger positive influence was seen after application of iodide with current (iontophoresis), as observed in a distinct improvement in break up time, fluorescein and rose bengal staining, and in a longer duration of this effect compared with the non-current group. No significant change in Schirmer test results and impression cytology were observed in both groups. CONCLUSIONS: Iodide iontophoresis has been demonstrated to be a safe and well tolerated method of improving subjective and objective dry eye factors in patients with ocular surface disease.     

丹参注射液电离子导入治疗玻璃体积血的疗效观察

目的:探讨丹参注射液电离子导入疗法在玻璃体积血患者中的临床应用价值。方法:选取2012-06/2013-06我院收治的玻璃体积血患者88例88眼,随机将患者分为观察组和对照组,每组44例44眼。对照组患者采用血栓通的临床药物治疗方案,而观察组患者则在此基础之上加用丹参注射液电离子导入的临床药物治疗方案,并分别对两组患者的临床治疗情况和视力恢复情况进行深入细致的比较和分析。结果:观察组患者治愈率和总有效率分别为75%和95%,均显著高于对照组患者的59%和77%,差别均具有统计学意义(P<0.05);与对照组患者相比,观察组患者视力处于0.6～0.9之间的比率明显提高,而处于0.2以下的比率则显著降低,同时观察组患者的全血比黏度、血浆比黏度、红细胞压积、纤维蛋白原等相关指标均明显改善,差别均具有统计学意义(P<0.05)。结论:丹参注射液电离子导入疗法对于玻璃体积血患者临床治疗效果的提升以及视力功能的改善均具有积极的促进作用。