Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection

PURPOSE: To describe the pharmacokinetics occurring after the direct injection of triamcinolone acetonide into the vitreous humor of humans. DESIGN: Interventional case series. PARTICIPANTS: Five patients who received a single 4-mg intravitreal injection of triamcinolone acetonide. METHODS: An aqueous humor sample was obtained from 5 eyes via an anterior chamber paracentesis at days 1, 3, 10, 17, and 31 after injection. At each visit, visual acuity and intraocular pressure were measured and indirect ophthalmoscopy was performed. A fluorescein angiogram was carried out at day 10. Concentrations were determined using high performance liquid chromatography; pharmacokinetic analysis was carried out using PK Analyst, an iterative, nonlinear, weighted, least-squares regression program. MAIN OUTCOME MEASURES: Intraocular concentrations of triamcinolone were measured and population pharmacokinetic parameters were calculated. RESULTS: Pharmacokinetic data followed a two-compartment model. Peak aqueous humor concentrations ranged from 2151 to 7202 ng/ml, half-lives from 76 to 635 hours, and the integral of the area under the concentration-time curve (AUC(0-t)) from 231 to 1911 ng/h per milliliter. After a single intravitreal injection of triamcinolone, the mean elimination half-life was 18.6 days in nonvitrectomized patients. The half-life in a patient who had undergone a vitrectomy was shorter at 3.2 days. CONCLUSIONS: There was considerable intrasubject variation among peak concentration, AUC(0-t) values, and elimination half-lives. After intravitreal injection, measurable concentrations of triamcinolone would be expected to last for approximately 3 months (93 +/- 28 days) in the absence of a vitrectomy. Because triamcinolone pharmacokinetics were characterized only in elderly patients with macular edema, the results cannot be extrapolated to other patient populations.     

Retinal vascular changes following intravitreal ranibizumab injections for neovascular AMD over a 1-year period

Purpose

To assess retinal vascular calibre changes in eyes with neovascular age-related macular degeneration (AMD), treated with intravitreal anti-vascular endothelial growth factor agents, over a 1-year period and compare any such changes to untreated fellow eyes.

Methods

Treatment naïve patients with neovascular AMD received three consecutive intravitreal injections of ranibizumab, followed by a pro re nata dosing regimen up to 1 year, with the aim of maintaining a ‘fluid-free'' macula. Retinal arteriolar and venular calibre was measured from digital fundus photographs at baseline and at three monthly intervals to 1 year, and summarised as central retinal artery equivalent (CRAE) and central retinal venular equivalent (CRVE), respectively.

Results

A total of 53 injected eyes and 41 fellow, non-injected eyes were analysed. At baseline, there were no differences in retinal vascular calibre between injected and non-injected eyes (mean CRAE (SD) 144.93 (14.07) vs 145.74 (13.10) μm, P=0.80 and mean CRVE (SD) 216.23 (25.93) vs 219.91 (22.82) μm, P=0.53). Over a 12-month period, retinal venular calibre dilatation occurred in injected eyes (mean CRVE change +5.71 (14.71) μm, P=0.007), with no change in retinal arterioles, +0.69 (14.71) μm, P=0.68. In non-injected eyes, arteriolar narrowing occurred as a whole, mean CRAE change −4.20 (7.00) μm, P=0.001, over 12 months, with a trend for narrowing in venules, −2.16 (11.56) μm, P=0.28. In injected eyes, after controlling for covariates, the changes in CRVE over 12 months mirrored improvements in macular thickness, −0.06 (−0.005, −0.11) μm, P=0.04, and visual acuity, +9.66 (−0.30, +19.32) μm, P=0.06.

Conclusion

Intravitreal ranibizumab significantly dilated retinal venules after a 1-year period.     

Long-term results of fluocinolone acetonide intravitreal implant in Behçet intractable posterior uveitis

Objective

To evaluate the long-term efficacy and safety of the fluocinolone acetonide intravitreal implant in patients with Behçet disease with intractable noninfectious posterior uveitis.

Design

Consecutive retrospective analysis.

Participants

Eight eyes from 7 patients with Behçet uveitis who did not respond successfully to conventional treatment with topical and systemic steroids and/or systemic steroid-sparing agents were studied.

Methods

We performed a chart review of patients who were treated with a 0.59-mg fluocinolone acetonide intravitreal implant at a single centre from September 2007 through June 2009. Snellen visual acuity, control of inflammation, and the development of complications such as infection or uncontrollable intraocular pressure (IOP) elevation were evaluated.

Results

Mean age at implant placement was 35.3 (range 17–42) years. Mean follow-up duration was 47.8 (range 39.5–57.6) months. Postoperative visual acuity improved by more than 3 lines in 6 eyes (75%). Five patients were able to discontinue all systemic medications. Six eyes (75%) exhibited postoperative IOP spikes of more than 30 mm Hg. Five patients required glaucoma shunting surgery postoperatively for IOP control. The single phakic eye developed a visually significant posterior subcapsular lens opacification that required cataract extraction. There was 1 case of postoperative cytomegalovirus endothelitis. Infection was controlled with oral valganciclovir and topical antibiotic medication, and the patient did not require implant removal.

Conclusions

The fluocinolone implant is effective in the control of intractable inflammation in Behçet uveitis. Elevation of IOP remains a major potential complication, and the possibility of infection should be considered.     

Ocular manifestations of syphilis: recent cases over a 2.5-year period

Background  

The ocular manifestations of syphilis are protean and can affect every structure of the eye. There has been a recent increase of syphilis infection in Europe. We report recent cases of ocular syphilis infection in a tertiary center.     

Safety and pharmacokinetics of a preservative-free triamcinolone acetonide formulation for intravitreal administration

PURPOSE: The safety and pharmacokinetics of a triamcinolone acetonide (TA) preservative-free (TA-PF) formulation were investigated after intravitreal administration in rabbits. METHODS: A TA-PF formulation was prepared as a sterile 40-mg/mL or 160-mg/mL suspension in single-use vials by adding TA powder to 0.5% hydroxypropyl methylcellulose in normal saline. TA-PF (4-mg and 16-mg doses) and Kenalog (Bristol-Myers-Squibb, Princeton, NJ) (4-mg dose) were injected into the vitreous of separate groups of rabbits, and drug levels were measured in the vitreous over time with HPLC. Ocular toxicology (clinical examination, serial electroretinography, and histopathologic analysis) was evaluated in a separate group of animals after intravitreal TA-PF injection. RESULTS: The half-lives of the injection amount in the vitreous, 4-mg TA-PF, 16-mg TA-PF, and 4-mg Kenalog, were found to be 24 days, 39 days, and 23 days, respectively. There were no signs of toxicities by clinical examination after TA-PF injection. Serial electroretinograms of rabbits receiving either 4-mg or 16-mg intravitreal TA-PF injections remained normal over time. Histopathologic analysis showed normal ocular tissues in animals receiving either 4-mg or 16-mg intravitreal TA-PF injections. CONCLUSION: The half-life of TA in the vitreous after a 4-mg injection of either TA-PF or Kenalog was comparable. A 16-mg dose of TA-PF produced a long vitreous half-life, and this may be of clinical benefit in patients requiring 6 months of drug exposure in the eye for a chronic disease.     

Persistent depot of triamcinolone acetonide after a single intravitreal injection

The persistence of depot of triamcinolone at four months following a single intravitreal injection is described.     

毛果芸香碱微乳滴眼剂及滴眼液在兔眼房水中的药代动力学研究

目的 对２％毛果芸香碱微乳滴眼剂与２％毛果芸香碱滴眼液兔房水中的药代动力学进行对比研究。方法 健康白兔６０只,随机分成２０组,１０个实验组,１０个对照组,每组３只兔（６只眼）。对各实验组双眼结膜囊内准确滴入２％毛果芸香碱微乳滴眼剂５０μｌ,对各对照组双眼同法滴入２％毛果芸香碱滴眼液５０μｌ,分别于给药后５、１０、３０、４０、６０、９０、１２０、１８０、２４０及３６０ｍｉｎ时抽取房水。用于氯甲烷提取     

Intravitreal pharmacokinetics and retinal concentrations of ganciclovir and foscarnet after intravitreal administration in rabbits

PURPOSE: To perform a detailed pharmacokinetic study and to evaluate the drug levels reached in the retina after the intravitreal administration of ganciclovir and foscarnet to rabbits. METHODS: Retinal and vitreal levels of both drugs were measured by high-performance liquid chromatography at 1, 6, 12, 24, 36, 48, 60, and 72 hours after a single intravitreal injection of 196 microg and 800 microg of ganciclovir and 960 microg of foscarnet to three groups of 24 pigmented rabbits. A noncompartmental pharmacokinetic analysis was used. RESULTS: Both drugs incorporated rapidly into the retina, but no equilibrium was observed between the drug levels in the vitreous humor and retina. Mean ganciclovir levels in vitreous and retina were 179.6 microg/g and 131.3 microg/g (dose of 196 microg), 755.7 microg/g and 381.6 microg/g (dose of 800 microg) at 1 hour after administration, decreasing to 0.1 microg/g, 0.6 microg/g, 0.8 microg/g, and 0.7 microg/g, respectively, by 72 hours. Mean foscarnet levels in vitreous and retina were 944 microg/g and 217.1 microg/g at 1 hour after administration, decreasing to 74 microg/g and 17.1 microg/g, respectively, by 72 hours. Whereas both doses of ganciclovir yielded retinal levels above the mean inhibitory concentration (IC50) of most human cytomegalovirus (CMV) isolates for more than 60 hours, foscarnet retinal levels were lower than the CMV IC50 before 36 hours had elapsed after administration. CONCLUSIONS: The results suggest that the intravitreal administration of ganciclovir has a better pharmacokinetic profile than foscarnet for the treatment of retinitis caused by CMV and other herpes viruses and support the administration of intravitreal ganciclovir twice a week as a treatment for CMV retinitis.     

Ocular pharmacokinetics in rabbits using a novel dual probe microdialysis technique

Ocular infections involve delicate internal structures of the eye that often require treatment with antimicrobial agents. A major constraint to the study of ocular drug absorption from systemic administration is the inaccessibility of the vitreous for continuous serial sampling. A novel dual probe microdialysis technique has been employed in our laboratory, which will enable the delineation of complete ocular pharmacokinetics of a drug. New Zealand albino rabbits weighing 2--2.5 kg were used. The animals were kept under anesthesia throughout the experiment. A concentric probe was implanted in the vitreous chamber about 3 mm below the corneal scleral limbus. Simultaneously a linear probe was implanted in the anterior chamber across the cornea. Intraocular pressure (IOP) was measured using Schiotz tonometer. The total protein concentrations in the aqueous and vitreous humors were determined using the Bio-Rad protein assay method. The aqueous and vitreous elimination kinetics of fluorescein were studied after intravitreal and systemic administrations over a period of 10 hr. Microdialysis technique was also compared to the conventional direct sampling technique by determining the intravitreal kinetics of fluorescein. Results suggest that IOP reverted to normal within 2 hr after the implantation of the probes. The increase in the vitreal total protein concentration was not significantly different from the baseline. The increase in the aqueous total protein concentration was less than five times the basal concentration throughout the experiment. The blood-aqueous and blood-retinal barrier integrity was delineated by determining the permeability index for fluorescein and were found to be 9.48 +/- 4.25% and 1.99 +/- 0.66% for the anterior and vitreous chamber, respectively. The rate constant of penetration of fluorescein into the anterior chamber was found to be 8.48 +/- 1.33 x 10(-2) min(-1), which was significantly higher than into the vitreous i.e. 4.34 +/- 2.82 x 10(-2) min(-1). The terminal elimination rate constant of fluorescein from the anterior chamber (1.48 +/- 0.79 x 10(-2) min(-1)) was found to be similar to that of the plasma terminal elimination rate constant (1.57 +/- 0.25 x 10(-2) min(-1)), but significantly higher than from the vitreous (3.0 +/- 0.7 x 10(-3) min(-1)). The terminal vitreal elimination rate constant of fluorescein after intravitreal administration was found to be similar by both microdialysis (3.98 +/- 0.6 x 10(-3) min(-1)) and direct sampling (4.38 +/- 1.4 x 10(-3) min(-1)) techniques. In case of direct sampling technique the area under the vitreous concentration-time curve was higher compared to that obtained by the microdialysis technique. There was no breakdown of the blood ocular barriers as shown by a very small change in the intraocular fluid protein concentrations. This was also confirmed by the fluorescein kinetics, which were in accordance with the previous studies. IOP data suggests that the intraocular fluid dynamics were not affected and the animals stabilized within 2 hr after the implantation of the probes. Fluorescein data suggests that the vitreous compartment is surrounded by a tighter barrier compared to the anterior chamber. This technique appears to be more sensitive, reproducible and requires only one animal for the determination of entire ocular pharmacokinetic profile.     

Safety of intravitreal triamcinolone acetonide:an electrophysiologic and histopathological study in rabbits

AIM: To evaluate the retinal safety of various doses of intravitreal triamcinolone acetonide (TA) in rabbits.Methods: Thirty New Zealand albino rabbits were divided into five groups (six animals each). In group 1 (control group), each animal received a single intravitreal injection of 0.1mL phosphate buffered saline. In groups 2, 3, 4 and 5, each rabbit received a single intravitreal injection of 4, 8, 16 and 32mg of TA, respectively. Each dose was contained in 0.1mL phosphate buffered saline. Clinical ocular examinations were performed before the injection and on the 1st, 3rd, 10th and 17th post-injection days. A standard dark adapted electroretinogram (ERG) was obtained before injection and on the 3rd, 10th and 17th post-injection days. After 17d, animals were sacrificed and their eyes prepared for pathological examination.RESULTS:By monitoring ERG as a functional index for the retina, intravitreal injection of 4mg TA showed no significant ERG changes. At doses of 8, 16 and 32, hyper-abnormal responses in a- and b- waves of ERG were detected on the 3rd post-injection day. These changes gradually returned back to normal limits after 17d. Histopathological examination of the retina of all animals showed no pathological changes.CONCLUSION: High doses of intravitreal TA seemed to have enhancing effects on the retinal function with gradual return to normal limits with no pathological changes detected in examined eyes.     

Safety of intravitreal triamcinolone acetonide:an electrophysiologic and histopathological study in rabbits

AIM

To evaluate the retinal safety of various doses of intravitreal triamcinolone acetonide (TA) in rabbits.

Methods

Thirty New Zealand albino rabbits were divided into five groups (six animals each). In group 1 (control group), each animal received a single intravitreal injection of 0.1mL phosphate buffered saline. In groups 2, 3, 4 and 5, each rabbit received a single intravitreal injection of 4, 8, 16 and 32mg of TA, respectively. Each dose was contained in 0.1mL phosphate buffered saline. Clinical ocular examinations were performed before the injection and on the 1st, 3rd, 10th and 17th post-injection days. A standard dark adapted electroretinogram (ERG) was obtained before injection and on the 3rd, 10th and 17th post-injection days. After 17d, animals were sacrificed and their eyes prepared for pathological examination.

RESULTS

By monitoring ERG as a functional index for the retina, intravitreal injection of 4mg TA showed no significant ERG changes. At doses of 8, 16 and 32, hyper-abnormal responses in a- and b- waves of ERG were detected on the 3rd post-injection day. These changes gradually returned back to normal limits after 17d. Histopathological examination of the retina of all animals showed no pathological changes.

CONCLUSION

High doses of intravitreal TA seemed to have enhancing effects on the retinal function with gradual return to normal limits with no pathological changes detected in examined eyes.     

Cyclocryotherapy: a review of cases over a 10-year period.

There are conflicting reports on the value of cyclocryotherapy in the management of glaucoma. This retrospective study was carried out to assess the efficacy and complication rate of this procedure. The case notes of all patients undergoing cyclocryotherapy at a single centre over a 10-year period were reviewed. Case records were available for 68 eyes of 64 people. Thirty-eight eyes had neovascular glaucoma, nine had aphakic glaucoma, nine had angle closure glaucoma, three had primary open angle glaucoma, and nine had secondary open angle glaucoma. The mean follow-up periods for these groups varied from 2.0-6.3 years. The mean reduction in intraocular pressure following treatment varied from 7.9 mm Hg in the secondary open angle glaucoma group to 24.3 mm Hg in those with angle closure glaucoma. Pressure was controlled in 29.4% overall, ranging from 66.7% in the angle closure and primary open angle groups to 0% in the secondary open angle group. Of the painful eyes 71% were rendered comfortable, indicating that pain relief from cyclocryotherapy is not due solely to pressure control. 30% of the patients lost their vision following the procedure, phthisis occurred in 11.8% and four eyes (5.9%) went on to enucleation. Our results indicate that cyclocryotherapy affords good pain relief, without good pressure control, in various types of glaucoma. While there is an apparent high complication rate, visual loss and phthisis cannot be ascribed directly to the procedure, since these are eyes with a poor prognosis.     

Epiretinal deposit of triamcinolone acetonide at the posterior pole after intravitreal injection.

The authors investigated possible toxic side effects of epiretinal triamcinolone acetonide deposits at the posterior pole after an intravitreal injection in both a vitrectomized and a non-vitrectomized eye. The vitrectomized eye developed massive epiretinal triamcinolone acetonide deposits at the posterior pole that were less pronounced in the non-vitrectomized eye. After resolution of the deposits, no morphologic signs of retinal toxicity were apparent. Mild scattered visual field defects did not correlate with the localization of the triamcinolone acetonide deposits. However, because recent in vitro studies indicate potential cytotoxicity, patients should be instructed to keep their heads in an upright position after intravitreal triamcinolone acetonide injection to avoid deposits at the posterior pole.     

毛果芸香碱透明质酸钠缓释滴眼剂在兔眼房水中的药代动力学研究

目的探讨0.5%毛果芸香碱透明质酸钠缓释滴眼剂滴眼后眼部的药代动力学特征,评价其相对生物利用度.方法选择健康白兔100 只,随机分为10个实验组和10个对照组,每组5只兔(10只眼).各实验组兔双眼结膜囊内均滴入0.5%毛果芸香碱透明质酸钠缓释滴眼剂50 μl,各对照组兔双眼亦滴入1%毛果芸香碱滴眼液50 μl.分别于给药后5、10、20、30、40、60、90、120、150及180 min抽取房水并对其定量分析.用二氯甲烷提取房水中的药物,采用反相高效液相色谱法(HPLC)测定房水中的药物浓度.药代动力学参数采用3p87药代动力学计算软件计算机拟合求得.结果采用反相HPLC法可以将毛果芸香碱与其它杂质很好分离,最低检测浓度为0.025 μg/ml.毛果芸香碱在房水中的回收率平均为98.2%.实验组和对照组给药后药物房水达峰时间分别为10 min和20 min, 达峰浓度分别为4.46 μg/ml和2.25 μg/ml, 药物消除半衰期分别为31.83 min和22.98 min.实验组药物的房水浓度-时间曲线下面积(AUC0～180)是对照组的1.75倍.实验组房水药物达峰浓度是对照组的1.98倍(P<0.05).结论 0.5%毛果芸香碱透明质酸钠缓释滴眼剂与1%毛果芸香碱滴眼液比较,达峰时间提前,达峰浓度增高,消除半衰期延长,提示其相对生物利用度提高,作用时间延长.