Shailaja Valluri

Drug-induced uveitis.

Uveitis has been reported in association with a variety of topical, intraocular, periocular, and systemic medications. To establish causality of adverse events by drugs, in 1981, Naranjo and associates proposed seven criteria, which are related to the frequency and documentation of the event; circumstances of occurrence, recovery, and recurrence; and coexistence of other factors or medications. Rarely does a drug meet all seven criteria. The authors review reports of drug-associated uveitis, applying the seven criteria and examining possible mechanisms. Only systemically administered biphosphonates and, perhaps, topical metipranolol meet all seven criteria. Systemic sulfonamides, rifabutin, and topical glucocorticoids fulfill at least five criteria.

Combination treatment of intraocular lymphoma.

Background: Primary intraocular lymphoma is an uncommon clinical entity with poor visual and systemic prognosis. Optimal management of intraocular lymphoma remains uncertain. Methods: Three patients with intraocular lymphoma, two of whom had documented CNS involvement, were treated based on a modification of the Sloan-Kettering Cancer Center protocol for primary CNS lymphoma. All patients underwent diagnostic pars plana vitrectomy and histopathologic confirmation of primary intraocular large B-cell lymphoma. Treatment involved systemic chemotherapy with methotrexate and high-dose ARA-C, radiation therapy of the brain and orbits, and intrathecal methotrexate delivered via an Ommaya reservoir. Results: Resolution of the ocular lymphoma was seen in all three patients, and resolution of the intracranial disease also was seen in the two patients with CNS involvement. All patients have remained disease free, with lymphoma in remission for at least 24 months after completion of treatment. Conclusion: The Sloan-Kettering protocol for the treatment of primary CNS lymphoma also appears to be effective in some cases of primary intraocular large cell lymphoma. Furthermore, the Ommaya reservoir works well for intrathecal delivery of methotrexate in patients with CNS or leptomeningeal spread.

Use of the Leksell Gamma Knife for localized small field lens irradiation in rodents.

For most basic radiobiological research applications involving irradiation of small animals, it is difficult to achieve the same high precision dose distribution realized with human radiotherapy. The precision for irradiations performed with standard radiotherapy equipment is ±2 mm in each dimension, and is adequate for most human treatment applications. For small animals such as rodents, whose organs and tissue structures may be an order of magnitude smaller than those of humans, the corresponding precision required is closer to ±0.2 mm, if comparisons or extrapolations are to be made to human data. The Leksell Gamma Knife is a high precision radiosurgery irradiator, with precision in each dimension not exceeding 0.5 mm, and overall precision of 0.7 mm. It has recently been utilized to treat ocular melanoma and induce targeted lesions in the brains of small animals. This paper describes the dosimetry and a technique for performing irradiation of a single rat eye and lens with the Gamma Knife while allowing the contralateral eye and lens of the same rat to serve as the “control”. The dosimetry was performed with a phantom in vitro utilizing a pinpoint ion chamber and thermoluminescent dosimeters, and verified by Monte Carlo simulations. We found that the contralateral eye received less than 5% of the administered dose for a 15 Gy exposure to the targeted eye. In addition, after 15 Gy irradiation 15 out of 16 animals developed cataracts in the irradiated target eyes, while 0 out of 16 contralateral eyes developed cataracts over a 6-month period of observation. Experiments at 5 and 10 Gy also confirmed the lack of cataractogenesis in the contralateral eye. Our results validate the use of the Gamma Knife for cataract studies in rodents, and confirmed the precision and utility of the instrument as a small animal irradiator for translational radiobiology experiments.

Levels of bimatoprost acid in the aqueous humour after bimatoprost treatment of patients with cataract.

Aim: To determine the aqueous humour concentration of the acid hydrolysis products of bimatoprost and latanoprost after a single topical dose of bimatoprost 0.03% or latanoprost 0.005% in humans. Methods: Randomised, controlled, double-masked, prospective study. 48 eyes of 48 patients scheduled for routine cataract surgery were randomised in an 8:2:2 ratio to treatment with a single 30 μl drop of bimatoprost 0.03%, latanoprost 0.005% or placebo at 1, 3, 6 or 12 h before the scheduled cataract surgery. Aqueous humour samples were withdrawn at the beginning of the surgical procedure and analysed using high-performance liquid chromatography–tandem mass spectrometry. Results: Bimatoprost acid (17-phenyl trinor prostaglandin F2α) was detected in aqueous samples at a mean concentration of 5.0 nM at hour 1, 6.7 nM at hour 3 and 1.9 nM at hour 6 after bimatoprost treatment. After latanoprost treatment, the mean concentration of latanoprost acid (13,14-dihydro-17-phenyl trinor prostaglandin F2α) in aqueous samples was 29.1 nM at hour 1, 41.3 nM at hour 3 and 2.5 nM at hour 6. Acid metabolites were below the limit of quantitation in all samples taken 12 h after dosing and in all samples from placebo-treated patients. None of the samples from latanoprost-treated patients contained quantifiable levels of non-metabolised latanoprost. Non-metabolised bimatoprost was detected in aqueous samples at a mean concentration of 6.6 nM at hour 1 and 2.4 nM at hour 3 after bimatoprost treatment. Conclusions: Low levels of bimatoprost acid were detected in aqueous humour samples from patients with cataract treated with a single dose of bimatoprost. Latanoprost acid concentrations in samples from patients treated with latanoprost were at least sixfold higher. These results suggest that bimatoprost acid in the aqueous humour does not sufficiently account for the ocular hypotensive efficacy of bimatoprost.

Ocular toxicity associated with systemic drug therapy.

Systemic drug-induced ocular side effects are increasing because of the vast numbers of new drugs being introduced. Reports of drug-induced ocular toxicity must be well documented, and other causes of these side effects must be ruled out to help establish causality. We reviewed the most recent reports of the most commonly used and newest systemic drugs that have been implicated in ocular toxicity. Using toxicologic criteria needed to establish causality, data from reports of ocular toxicity associated with systemic cidofovir (Vistide), sildenafil (Viagra), vigabatrin (Sabril), tamoxifen (Nolvadex), hydroxychloroquine (Plaquenil)/chloroquine (Aralen), amiodarone (Cordarone), and lovastatin (Mevacor)/simvastatin (Zocor) were evaluated and summarized. The probability for causality was determined to be high for all these drugs except for vigabatrin and lovastatin/simvastatin. Methods for detecting, preventing, and treating ocular toxic reactions were then reviewed for each drug.

Estrogen Protects against Radiation-Induced Cataractogenesis

Abstract Dynlacht, J. R., Valluri, S., Lopez, J., Greer, F., DesRosiers, C., Caperell-Grant, A., Mendonca, M. S. and Bigsby, R. M. Estrogen Protects against Radiation-Induced Cataractogenesis. Radiat. Res. 170, 758–764 (2008). Cataractogenesis is a complication of radiotherapy when the eye is included in the treatment field. Low doses of densely ionizing space radiation may also result in an increased risk of cataracts in astronauts. We previously reported that estrogen (17-β-estradiol), when administered to ovariectomized rats commencing 1 week before γ irradiation of the eye and continuously thereafter, results in a significant increase in the rate and incidence of cataract formation and a decreased latent period compared to an ovariectomized control group. We therefore concluded that estrogen accelerates progression of radiation-induced opacification. We now show that estrogen, if administered continuously, but commencing after irradiation, protects against radiation cataractogenesis. Both the rate of progression and incidence of cataracts were greatly reduced in ovariectomized rats that received estrogen treatment after irradiation compared to ovariectomized rats. As in our previous study, estradiol administered 1 week prior to irradiation at the time of ovariectomy and throughout the period of observation produced an enhanced rate of cataract progression. Estrogen administered for only 1 week prior to irradiation had no effect on the rate of progression but resulted in a slight reduction in the incidence. We conclude that estrogen may enhance or protect against radiation cataractogenesis, depending on when it is administered relative to the time of irradiation, and may differentially modulate the initiation and progression phases of cataractogenesis. These data have important implications for astronauts and radiotherapy patients.

Effect of Estrogen on Radiation-Induced Cataractogenesis

Abstract Dynlacht, J. R., Tyree, C., Valluri, S., DesRosiers, C., Caperell-Grant, A., Mendonca, M. S., Timmerman, R. and Bigsby, R. M. Effect of Estrogen on Radiation-Induced Cataractogenesis. Radiat. Res. 165, 9–15 (2006). Cataractogenesis is a widely reported late effect that is observed in patients receiving total-body irradiation (TBI) prior to bone marrow transplantation or radiotherapy for ocular or head and neck cancers. Recent studies indicate that estrogens may protect against age-related and drug-induced cataracts. Moreover, other reports suggest that estrogen possesses antioxidant properties. Since the effect of estrogen on radiation cataractogenesis is unknown, we wished to determine whether estrogen modulates radiation-induced opacification of the lens. Intact or ovariectomized Sprague-Dawley rats were treated with either 17-β-estradiol or an empty silastic capsule. The right orbit was then irradiated with either 10 or 15 Gy of 60Co γ rays using a Leksell Gamma Knife, and lenses were examined at various times postirradiation with a slit lamp or evaluated for light transmission. We found that for ovariectomized rats irradiated with 15 Gy, the lens opacity and the incidence of cataract formation in the estradiol-treated group were significantly increased compared to the control group at the end of the 25-week period of observation. Cataract incidence was also high in irradiated eyes of ovary-intact animals at 25 weeks postirradiation but was greatly reduced in the ovariectomized control group, with less than half of irradiated eyes showing evidence of cataractogenesis. Thus, after irradiation with 15 Gy of γ rays, estrogen increased the incidence of cataract formation. We also observed that although the incidence of cataract formation in rats irradiated with 10 Gy and receiving continuous estrogen treatment was not altered compared to rats in the control group that did not receive estrogen, the latent period for posterior subcapsular cataract formation decreased and the severity of the anterior cataract increased. Taken together, our data suggest that estrogen accelerates progression of radiation-induced opacification.

Effect of gender on radiation-induced cataractogenesis

Abstract Henderson, M. A., Valluri, S., DesRosiers, C., Lopez, J. T., Batuello, C. N., Caperell-Grant, A., Mendonca, M. S., Powers, E., Bigsby, R. M. and Dynlacht, J. R. Effect of Gender on Radiation-Induced Cataractogenesis. Radiat. Res. 172, 129-133 (2009). Radiation cataractogenesis is an important consideration for radiotherapy patients and for astronauts. Data in the literature suggest that gender and/or estrogen may play a role in the incidence of age-related cataracts. However, few data exist on the effect of gender on radiation-induced cataractogenesis. We compared the incidence and rate of progression of cataracts induced by ionizing radiation in male and female Sprague-Dawley rats. Male rats were implanted with either an empty silastic capsule or a capsule containing 17-β-estradiol. Ovary-intact female rats were implanted with empty capsules. All rats received a single dose of 10 Gy (60Co γ rays) to the right eye only. Lens opacification was measured at 2–4-week intervals with a slit lamp. The incidence of radiation-induced cataracts was significantly increased in male rats compared to female rats (P  =  0.034). There was no difference in the rate of cataract progression between the three groups. Our data suggest there is a gender-related difference in radiation-induced cataractogenesis, but the increased incidence of radiation cataractogenesis in male rats compared to female rats cannot be attributed to estrogen levels, since there was no difference in cataract incidence between male rats implanted with empty capsules and those implanted with capsules containing 17-β-estradiol.

Ovarian Hormone Modulation of Radiation-Induced Cataractogenesis: Dose-Response Studies

PURPOSE Epidemiologic data on the effects of female sex hormones in cataract formation are conflicting. With the use of a rat model of radiation-induced cataractogenesis, it was found that estrogen can either enhance or inhibit the progression of radiation cataracts, depending on when the hormone is administered. The present study was performed to further define radiation-hormone interactions during cataractogenesis. METHODS In one experiment, rats were left ovary-intact or ovariectomized and were then irradiated with 2.5, 5, 10, or 15 Gy to one eye. In another experiment, ovariectomized rats were treated continuously with three different doses of estradiol through a slow-release capsule implanted subcutaneously, after which one eye was irradiated with 15 Gy. In all animals, cataract formation was followed by slit lamp examination at regular intervals. RESULTS Latency to identification of cataracts decreased exponentially with increasing radiation dose. The presence of ovaries enhanced cataractogenesis when the eye was irradiated with 15 Gy, but there was no difference between ovary-intact and ovariectomized rats that were irradiated at lower doses. In ovariectomized rats irradiated with 15 Gy, estradiol increased the rate of progression of cataracts in a dose-dependent manner. The rate of cataract progression increased linearly with increasing estradiol dose; there was no sign of saturation at high estradiol doses, as would be expected from a receptor-mediated effect. CONCLUSIONS Ovarian hormones enhance radiation-induced cataract formation; hormone supplementation experiments indicate that estrogen is responsible for this effect. The data suggest that the enhancing effect of estradiol is not mediated by its receptor, but this requires further study.

Age and Hormonal Status as Determinants of Cataractogenesis Induced by Ionizing Radiation. I. Densely Ionizing (High-LET) Radiation

Abstract Astronauts participating in extended lunar missions or the projected mission to Mars would likely be exposed to significant doses of high-linear energy transfer (LET) heavy energetic charged (HZE) particles. Exposure to even relatively low doses of such space radiation may result in a reduced latent period for and an increased incidence of lens opacification. However, the determinants of cataractogenesis induced by densely ionizing radiation have not been clearly elucidated. In the current study, we show that age at the time of exposure is a key determinant of cataractogenesis in rats whose eyes have been exposed to 2 Gy of 56Fe ions. The rate of progression of cataractogenesis was significantly greater in the irradiated eyes of 1-year-old rats compared to young (56-day-old) rats. Furthermore, older ovariectomized rats that received exogenous estrogen treatment (17-β-estradiol) commencing 1 week prior to irradiation and continuing throughout the period of observation of up to approximately 600 days after irradiation showed an increased incidence of cataracts and faster progression of opacification compared to intact rats with endogenous estrogen or ovariectomized rats. The same potentiating effect (higher incidence, reduced latent period) was observed for irradiated eyes of young rats. Modulation of estrogen status in the 1-year-old animals (e.g., removal of estrogen by ovariectomy or continuous exposure to estrogen) did not increase the latent period or reduce the incidence to that of intact 56-day-old rats. Since the rapid onset and progression of cataracts in 1-year-old compared to 56-day-old rats was independent of estrogen status, we conclude that estrogen cannot account for the age-dependent differences in cataractogenesis induced by high-LET radiation.