Intravitreal drug therapy

The treatment of many ocular disorders is hampered because of poor penetration of systemically administered drugs into the eye. The tight junctional complexes (zonulae occludens) of the retinal pigment epithelium and retinal capillaries are the site of the blood-ocular barrier. This barrier inhibits penetration of substances, including antibiotics, into the vitreous. Over the last 18 years we have evaluated the nontoxic doses of various drugs. These include antibiotics and antifungals for treatment of bacterial and fungal endophthalmitis, antivirals for treatment of viral retinitis (specifically, when medication with these drugs poses the threat of toxicity to other organs). Intravitreal antineoplastic drugs have been studied to prevent cell proliferation in the vitreous cavity after retinal attachment surgery, which can lead to proliferative vitreoretinopathy (PVR). Furthermore, we evaluated the anti-inflammatory action of dexamethasone and cyclosporine A to reduce intraocular inflammation after intraocular surgery or in uveitis. Because these studies had been performed in the presence of the vitreous, which can slow down the diffusion of the drugs toward the retina, it was necessary to reevaluate the concentration of drugs which could be administered intravitreally in the vitrectomized eye. The nontoxic dose of numerous drugs when added to vitrectomy infusion fluid has also been evaluated. Furthermore, the role of vitrectomy in the treatment of bacterial fungal endophthalmitis has been studied and the role of vitrectomy in this ocular disorder is defined.     

Intravitreal administration of drugs

The direct intravitreal administration represents the easiest and quickest method for obtaining efficient substance concentrations closer to the lesions and is reserved to the pathology which is resistant to the common treatments.     

Intravitreal penetration of cefepime after systemic administration to humans

PURPOSE: To investigate the penetration of cefepime (a fourth-generation cephalosporin) into the vitreous after single-dose intravenous administration to human subjects. METHODS: Thirty phakic patients about to undergo vitreous surgery received 1 g (group 1, 15 patients) or 2 g cefepime (group 2, 15 patients) in a single intravenous injection before surgery. The indications for vitreous surgery were retinal detachment with proliferative vitreoretinopathy (24 patients), retinal detachment associated with giant retinal tear (4 patients), macular hole (1 patient) and intraocular foreign body (1 patient). Samples of vitreous and serum were obtained at 0.5, 1, 2, 4 and 12 h after injection. Three patients were used for each sampling time and for 1 g and 2 g of cefepime. Samples were assayed for cefepime concentrations with high-performance liquid chromatography (HPLC). RESULTS: All the patients had detectable cefepime in their vitreous and serum measurable by HPLC. The level of cefepime in the vitreous peaked at 2 h and reached a minimum at 12 h after intravenous injection in both groups. A mean peak vitreous level of cefepime was 1.91 +/- 0.13 microg/ml in group 1 and 2.86 +/- 0.37 microg/ml in group 2. The level of cefepime in the vitreous at 12 h after injection was 0.89 +/- 0.14 microg/ml in group 1 and 0.97 +/- 0.30 microg/ml in group 2. CONCLUSION: The vitreous level of cefepime after intravenous injection was below the minimum inhibitory concentration (MIC(90)) against Staphylococcus aureus, Staphylococcus epidermidis and Pseudomonas aeruginosa, but was over the MIC(90) against Proteus mirabilis, Klebsiella spp., Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes and Enterobacter spp.     

Intravitreal drug delivery by microspheres of biodegradable polymers

We evaluated the efficacy of microspheres of biodegradable polymers as a slow releasing drug delivery system in the vitreous body. Microspheres containing 5-FU were prepared with polymers of poly-(lactic acid) or copolymers of glycolic acid and lactic acid. The release of the drug was studied in vitro. Poly-(lactic acid) microspheres released 5-FU for 7 days. The intravitreal kinetics of the microspheres was studied in rabbits in vivo. The microspheres disappeared from the vitreous cavity of normal eyes by 48 +/- 5 days after injection. Disappearance was accelerated from the vitreous cavity of vitrectomized rabbits (14 +/- 2 days, p less than 10(-6)). No abnormality was found on electroretinographic or histological examinations after microspheres injection. These results suggested that microspheres of biodegradable polymers could be useful as a potential drug delivery system for sustained drug release in the vitreous body.     

玻璃体腔注药治疗外因性眼内炎

目的 :评估玻璃体腔注药治疗外因性感染性眼内炎的疗效。方法 :回顾 1999年 7月～ 2 0 0 2年 2月我院收治的首诊时即给予玻璃体腔注药的外因性感染性眼内炎患者19例 19眼 ,平均年龄为 42 .4岁。其中白内障摘除联合人工晶体植入术后 5眼 ,眼球穿孔伤后 14眼。结果 :随访 5～ 35个月 ,玻璃体腔注药后炎症控制 9眼 ,治疗后视力在 0 .0 5以上者 8眼 ,有效率为 42 .1%。结论 :玻璃体腔注药治疗感染性眼内炎仍有一定的疗效     

Intravitreal administration of antisense oligonucleotides: potential of liposomal delivery

Antisense oligonucleotides are short synthetic fragments of genes that are able to inhibit gene expression after being internalized by cells. They can therefore be used as antiviral compounds particularly, for the treatment of ocular viral infections (i.e. Herpes simplex virus or Cytomegalovirus, CMV). Antisense oligonucleotides are however poorly stable in biological fluids and their intracellular penetration is limited. Although oligonucleotides are now currently used in therapeutics for the treatment of CMV by intravitreal injection (Vitravene) their main drawbacks impose to repeat the number of administrations which can be very harmful and damaging. A system that is able to permit a protection of oligonucleotides against degradation and their slow delivery into the vitreous would be more favorable for improving patient compliance. The use of liposomes for intravitreal administration can be very promising since these lipid vesicles are able to protect oligonucleotides against degradation by nucleases and they allow to increase the retention time of many drugs in the vitreous. In this review, the potentialities of liposomes for the intravitreal delivery of oligonucleotides will be discussed.     

Intravitreal endoscopic visualization of intraocular ganciclovir devices: improved long-term treatment of CMV retinitis

BACKGROUND: The recent development of 20- and 19-gauge diameter endoscopes allows an excellent direct intravitreal visualization of intraocular morphology. A gradient index (GRIN) endoscope (Insight Instruments, Lake Mary, FL, USA), which combines a small diameter (0.89 mm, 20 gauge) and an exceptional optical resolution, can be used as a diagnostic tool for the assessment of the safety and vitreous interaction of sustained release intraocular devices which have been designed to deliver ganciclovir (Vitrasert) over a period of 8-12 months and were successively implanted in several eyes. PATIENTS AND METHODS: 78 eyes of 49 patients received 100 ganciclovir implants between November 1995 and July 1998. In six patients who received additional implants, the GRIN endoscope was used as an optical control of wound healing processes and Vitrasert positioning after implantation of prior devices (two-point suturing technique). RESULTS: In all of these six eyes, a clinical stabilization of the cytomegalovirus retinitis was noted. Endoscopic observation of the scleral 5-mm incision revealed no gaps after two-point suturing of the device. Only one of six eyes showed significant vitreous tractions around the Vitrasert. However, the struts of all pellets were completely covered by a fibrous membrane. Occasional fibrous plaques were noted on the surface of devices which presumably had been damaged by surgical manipulations. In one case, the endoscopic examination disclosed the suprachoroidal implantation of a device. In this eye, no signs of retinal toxicity or recurrence of CMV retinitis were observed. CONCLUSIONS: High resolution endoscopy of the vitreous cavity appears to be an effective method for the control of intraocular drug delivery devices. Basically, the repeated implantation of intraocular ganciclovir implants can be considered a safe method in the management of relapsing CMV retinitis. However, the endoscopic observation of fibrous membranes covering the struts suggest that the explanation of an intraocular device has the potential for various intraoperative complications (e.g. hemorrhages, traction, tears, retinal detachment). Therefore, we would recommend the additional implantation of further implants rather than a replacement.     

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.     

Intravitreal angiostrongyliasis

A case of intravitreal angiostrongyliasis is reported in a Thai female who had eaten raw snails. After immobilising the worm by use of an intravitreal cryoprobe it was successfully removed via the pars plana with vitreous foreign body forceps.     

Foveal Exudative Macroaneurysm Treated with Intravitreal Ranibizumab

PurposeWe report a case of a foveal macroaneurysm with long-standing macular edema in a rare location, successfully treated with intravitreal ranibizumab.MethodsWe report the case of a 52-year-old man with left eye long-term visual loss due to macular edema caused by a retinal macroaneurysm, localized about 400 μm from the center of the fovea, and its response to 6 monthly ranibizumab intravitreal injections. His best-corrected visual acuity and morphological data evaluated by optical coherence tomography and fluorescein angiography are presented.ResultsHis best-corrected visual acuity improved from 1/10 to 3/10 after the 3rd injection, and from 1/10 to 4/10 after the 6th one. The central retinal thickness was evaluated by optical coherence tomography and improved from 310 to 233 μm, with the resolution of both the associated serous detachments and the cystoid macular edema; an almost complete reabsorption of the hard exudates at the end of the treatment was also observed. The macroaneurysm lumen almost obliterated after the 3rd injection and completely collapsed at the end of treatment.ConclusionsIntravitreal ranibizumab may be effective in the treatment of long-standing macular edema associated with foveal macroaneurysms. To the best of our knowledge, this is the first report of a retinal macroaneurysm located so close to the foveal avascular zone.Key Words: Exudative retinal macroaneurysm, Fovea, Intravitreal ranibizumab