Paul M. Beer

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.

The effect of intravitreal triamcinolone acetonide on intraocular pressure.

BACKGROUND AND OBJECTIVE To ascertain whether a single 4-mg intravitreal triamcinolone acetonide injection is associated with elevated intraocular pressure (IOP). PATIENTS AND METHODS Retrospective noncomparative interventional case series. Forty-three consecutive eyes of 38 patients who had 12 weeks of follow-up were included. The IOPs before and after triamcinolone acetonide treatment were recorded by Goldmann applanation at each patient visit. RESULTS Within 12 weeks after intravitreal triamcinolone acetonide injection, 21 of 43 eyes (48.8%) demonstrated an increase in IOP of 5 mm Hg or greater, and 12 of 43 eyes (27.9%) had an increase in IOP of 10 mm Hg or greater. The mean time for an increase in IOP of 5 mm Hg or greater to occur was 4.1 weeks (standard deviation = 4.8 weeks), and the mean time to reach maximum IOP was 6.6 weeks (standard deviation = 5.1). The difference between the mean pre-injection IOP (15.12 mm Hg, n = 43) and the maximum post-injection IOP (20.74 mm Hg, n = 43) was statistically significant (P < .0001). CONCLUSION A single 4-mg intravitreal triamcinolone acetonide injection is associated with an increase in IOP of 10 mm Hg or greater in 27.9% of eyes after the first injection. All eyes responded to topical glaucoma medication.

Adverse events after intravitreal infliximab (Remicade).

Purpose: To determine the tolerability of intravitreal infliximab (Remicade) in patients with refractory diabetic macular edema or choroidal neovascularization secondary to age-related macular degeneration. Methods: This is a prospective, interventional, noncomparative, open-label, 12-week pilot study of intravitreal infliximab in four patients who failed conventional therapies. Two had diabetic macular edema and two had choroidal neovascularization secondary to age-related macular degeneration. All patients received 0.5 mg/0.05 mL intravitreal infliximab and were eligible for a second injection at 6 weeks if reinjection criteria were met. Outcome measures were best-corrected visual acuity using standard Early Treatment Diabetic Retinopathy Study refraction, central retinal thickness on optical coherence tomography, fluorescein angiography, standard electroretinography, and microperimetry. Patients were evaluated at Days 0 and 1 and Weeks 2, 6, and 12. Six months after study completion, all patients were tested for human antimouse and human antichimeric antibodies. Results: At Week 12, visual acuity scores had declined in three patients. All patients had persistence of cystoid macular edema on optical coherence tomography, although two had a decrease in central retinal thickness. Three patients had an overall worsened appearance on angiography. On the final electroretinography, all patients had a decrease in maximal combined responses, from 7% to 24% from baseline, which may have been within expected variability of electroretinography data. To photopic flicker stimulus, three patients had slower latency of response, and all had decreased amplitudes. All patients declined on microperimetry. The first patient entered in the study met the criteria for a second injection because of improved standard electroretinography and microperimetry at Week 6. However, 2 weeks after the second injection, he developed panuveitis. Two other patients, after one injection only, had evidence of inflammation (vitritis or panuveitis) on examination at Week 6. Three patients developed systemic antibodies against infliximab (human antichimeric antibodies). Conclusion: Low-dose intravitreal infliximab was not well tolerated in this small group of patients and was both immunogenic and probably retinotoxic.

Vitreous Penetration Of Topical Moxifloxacin And Gatifloxacin In Humans

Purpose: To determine the vitreous penetration of the new fourth-generation topical fluoroquinolones moxifloxacin 0.5% and gatifloxacin 0.3%. Methods: A prospective randomized clinical trial comprising 12 eyes of 12 patients scheduled for pars plana vitrectomy between August 2003 and September 2003 was performed in a clinical practice. The patients were randomly assigned to receive topical moxifloxacin 0.5% (n = 6) or gatifloxacin 0.3% (n = 6). One half the patients in each antibiotic group received 1 drop every 15 minutes for a total of 3 doses starting 1 hour before surgery, and the other one half self-administered the antibiotic drop 4 times daily for 3 days before surgery and at 7 am on the day of surgery. Undiluted vitreous samples were obtained and analyzed using high-performance liquid chromatography. Results: Either moxifloxacin 0.5% or gatifloxacin 0.3% was detected in the vitreous in all 12 patients in the study. There was no significant difference between the mean vitreous concentration of moxifloxacin 0.5% given over 1 hour preoperatively (0.012 ± 0.011 &mgr;g/mL) and that given in the 3-day regimen (0.011 ± 0.008 &mgr;g/mL) (P = 0.93). There was also no significant difference between the mean vitreous concentration of gatifloxacin 0.3% given over 1 hour preoperatively (0.001 ± 0.0003&mgr;g/mL) and that given over 3 days (0.008 ± 0.006 &mgr;g/mL) (P = 0.11). Vitreous concentrations of moxifloxacin 0.5% and gatifloxacin 0.3% in each eye were all lower than the 90% minimum inhibitory concentration for the commonest bacterial isolates causing endophthalmitis. With both dosing regimens, the mean vitreous concentration of moxifloxacin 0.5% was higher than that of gatifloxacin 0.3% administered at the same regimen, but this was not statistically significant. Conclusion: Both topical moxifloxacin 0.5% and gatifloxacin 0.3% penetrated the vitreous in the uninflamed eye, but the vitreous concentrations attained were all lower than the 90% minimum inhibitory concentration for the commonest bacterial pathogens causing acute postoperative endophthalmitis.

Intravitreal triamcinolone injection for diabetic macular edema: a clinical and fluorescein angiograhic case series

BACKGROUND A significant number of eyes with diabetic macular edema remain refractory to treatment despite numerous attempts at photocoagulation. Triamcinolone acetonide, a minimally water soluble steroid injected in suspension form, has been reported to be a well-tolerated agent for intravitreal injection, prompting a decrease in diabetic macular edema on optical coherence tomography. We report our experience with this treatment in 19 eyes with persistent diabetic macular edema. METHODS We reviewed the charts of 16 patients (19 eyes) from a clinical practice with diabetic macular edema persistent after focal or grid laser photocoagulation. All eyes had received 4 mg of triamcinolone, injected into the vitreous cavity 3.5 mm posterior to the limbus. Fluorescein angiography was performed before and about 2 weeks after the injection. Snellen visual acuity and intraocular pressure (as determined with Goldmann applanation tonometry) were also measured before and after the injection. RESULTS Fluorescein angiography showed marked improvement of macular edema in 4 eyes (21.0%), mild improvement in 10 eyes (52.6%) and no change in 5 eyes (26.3%); no patient had worsening of macular edema. Visual acuity improved by at least 1 line in 13 eyes (68.4%), by 2 or more lines in 5 eyes (26.3%), by 3 or more lines in 2 eyes (10.5%) and by 4 lines in 1 eye (5.3%); visual acuity remained unchanged in 5 eyes (26.3%) and deteriorated by 1 line in 1 eye (5.3%). Intraocular pressure elevation of 10 mm Hg or greater occurred in two eyes (10.5%) and was successfully treated with topical administration of 0.15% brimonidine.The triamcinolone was well tolerated, and there were no other ocular complications. INTERPRETATION Intravitreal injection of triamcinolone has potential in the treatment of diabetic macular edema and warrants investigation in a randomized prospective clinical trial.

Role of intravitreal triamcinolone acetonide in the treatment of postoperative endophthalmitis.

Purpose: To report the use of commercially available triamcinolone acetonide as adjunct treatment for acute-onset endophthalmitis after intraocular procedures. Methods: Charts of 14 patients who received intravitreal triamcinolone in combination with intravitreal antibiotics for treatment of acute endophthalmitis were reviewed. Patients were included if they presented with pain, vision loss, and severe anterior chamber reaction or hypopyon. Visual acuities, intraocular pressures, anterior chamber reaction, and view of fundus details were recorded at baseline, 1 day, 1 week, 1 month, and 3 months to 5 months. Results: Culture-positive results were found for 57% (8/14) of patients. Isolated species included Staphylococcus epidermidis, viridans streptococcus, group D Streptococcus (nonenterococcus), Propionibacterium acnes, and diphtheroid bacilli. Visual acuities improved an average of 7.5 Snellen lines. Preendophthalmitis level visual acuities were recovered in 78.6% patients (11/14), with 64% (9/14) of patients achieving visual acuity of 20/40 or better regardless of presenting vision. Resolution of anterior chamber reaction and view of fundus details were consistent with visual acuities. Conclusions: Intravitreal triamcinolone combined with intravitreal antibiotics appears to have a safety profile similar to current modalities with a favorable effect on visual recovery and function in the setting of acute postoperative endophthalmitis.

Choroidal neovascularization after radial optic neurotomy for central retinal vein occlusion.

A 69-year-old man was referred to the retina service with a diagnosis of CRVO in the right eye. His Snellen visual acuity was 20/60 in the right eye, Goldmann intraocular pressure was 13 mmHg in the right eye, and there was a relative afferent pupillary defect in the right eye. The appearance of the fundus was remarkable for diffuse intraretinal hemorrhages and optic nerve edema. Six weeks later his CRVO worsened substantially, with the development of confluent retinal hemorrhages and a mild vitreous hemorrhage. His vision had deteriorated to counting fingers at 2 feet. The patient consented to a radial optic neurotomy in the right eye, which was performed as described by Opremcak et al.1 A limited pars plana vitrectomy was performed and a microvitreoretinal blade (Alcon, Fort Worth, TX) was used to incise the optic nerve medially. On postoperative day 1, the patient’s vision was hand motion in the right eye and his fundus appearance was unchanged with a typical CRVO appearance and diffuse vitreous hemorrhage. The vitreous hemorrhage occurred postoperatively, and as such can be considered a complication of the procedure. He was treated with prednisolone acetate 1% (Pred Forte; Allergan, Irvine, CA) and ofloxacin 0.3% (Ocuflox; Allergan) eye drops four times daily. Two months postoperatively, the retinal hemorrhages had decreased and cystoid macular edema (CME) was still apparent. The patient was given an injection of 4 mg intravitreal triamcinolone (Kenalog-40; Bristol Myers Squibb, Peapack, NJ) in an attempt to treat the CME. Ten days after the intravitreal triamcinolone injection, intraocular pressure measured 56 mmHg. There was no evidence of iris or angle neovascularization and the pressure rise was presumed to be due to a steroid response. The patient was treated with oral acetazolamide 250 mg four times daily (Diamox; WyethAyerst, Pearl River, NY), topical bimatoprost 0.03% (Lumigan; Allergan), brimonidine 0.15% (Alphagan P; Allergan), and dorzolamide (Trusopt; Merck). The patient continued on topical glaucoma therapy for 6 months to control the intraocular pressure. Eight months after his initial presentation, his visual acuity was 20/400 and the intraocular pressure measured 11 mmHg. There was persistent macular edema and an epimacular membrane was noted. Macular grid laser was performed with argon green laser (Iridex; Mountain View, CA) at the following settings: 102 spots, 75 m spot size, 200 mW, 100 msec. Eight months after the radial optic neurotomy, his visual acuity had dropped back to counting fingers at 5 feet. Subretinal fluid was noted nasal to the optic disk at the site of the radial optic neurotomy. Fluorescein angiography revealed the presence of a choroidal neovascular membrane (CNV) located nasal to the optic nerve (Figure 1). Ablative thermal laser was performed to this CNV with argon green laser (Iridex) at the following settings: 143 spots, 300 m spot size, 400 msec duration, 514 mW. The CNV was found to be closed on fluorescein angiography both at 10 days and 2 months after laser photocoagulation (Figure 2). His visual acuity remained counting fingers at 6 feet. Disappointed with his postoperative course and the minimal visual improvement after radial optic neurotomy, the patient canceled all further follow-up visits.

Infliximab stability after reconstitution, dilution, and storage under refrigeration.

Purpose: The purpose of this study was to investigate the stability of reconstituted infliximab solutions and determine whether infliximab is suitable for compounding for potential intravitreal use. Methods: Infliximab was reconstituted, and the solution was aliquoted and stored refrigerated. On each day of testing, an aliquot was serially diluted to concentrations ranging from 50,000 pg/mL to 69 pg/mL. Each dilution was assayed by microsphere immunoassay daily for 5 days and weekly for a total of 6 weeks. The outcome measure was median fluorescence intensity measured by dual laser flow analysis of fluorochrome-labeled secondary antibodies to infliximab bound to tumor necrosis factor-α–coated microspheres. Results: There was an increasing median fluorescence intensity for increasing infliximab concentration in a sigmoidal dose–response curve with a variable slope that was equivalent for each time point. Each respective concentration of infliximab showed nearly equivalent median fluorescence intensity for every time point over the 6-week period. Conclusion: The authors found that the immunoreactivity of 2 different concentrations of infliximab stored at 4°C over a 6-week period remained stable. Infliximab is suitable for compounding and could be a cost-effective intravitreal medication for use in clinical practice if further study supports its safety and efficacy.

Analysis of the molecular biologic milieu of the vitreous in proliferative vitreoretinopathy.

Purpose: Previous investigations have explored molecular differences between proliferative vitreoretinopathy and primary retinal detachment. An exploration of a greater number of molecules might provide novel insight into the biology of this disorder and identify potential therapeutic targets. Methods: Vitreous specimens were obtained from patients with epiretinal membranes or macular puckers (n = 15), patients with a primary retinal detachment without proliferative vitreoretinopathy (n = 15), and patients with retinal detachments and proliferative vitreoretinopathy (n = 15). A multiplex assay was performed to calculate the concentrations of 48 different cytokines and chemokines, and statistical analyses were performed to identify differences between the groups. Results: Of the 48 molecules that were studied, we identified 10 that were statistically significantly different in cases of proliferative vitreoretinopathy, including interleukins 4, 5, 6, and 15; granulocyte–macrophage colony-stimulating factors; stem cell factor; stem cell growth factor; macrophage inflammatory protein 1&agr;; and interferon &ggr;–induced protein 10. Conclusion: Proliferative vitreoretinopathy represents a highly ordered molecular process that involves discrete changes in the concentrations of specific cytokines and chemokines. These molecules may represent novel therapeutic targets.

Intravitreal Triamcinolone Acetonide Use in Diabetic Macular Edema: Illustrative Cases

The role of intravitreal triamcinolone acetonide (IVTA) for patients with diabetic macular edema is controversial. Three diabetic macular edema case studies are presented to illustrate short-term outcomes. The main outcome measures included visual acuity (VA), optical coherence tomography (OCT), macular thickening (in microns), and improvement in visual acuity. IVTA appears to have short-term efficacy in selected patients with diabetic macular edema, and it is a reasonable treatment option for patients with very poor presenting VA. A controlled prospective study to evaluate the emerging role of IVTA in combination with other treatment options for diabetic macular edema, especially among patients with poor VA at presentation, is underway through the Diabetic Retinopathy Clinical Research network.