Repeated administration of adenovector in the eye results in efficient gene delivery

PURPOSE: To determine whether repeat administration of an adenovector (Ad) into the eye results in efficient gene delivery and to test whether transgenes can be expressed from an adenovector expression system in the presence of preexisting, neutralizing anti-Ad antibodies. METHODS: To assess the efficiency of repeated gene delivery of an adenovector expression system, C57Bl/6 mice received one, two, or three injections (intravitreal [IVT] or periocular [PO]) of AdNull.11D (empty cassette) at 2-week intervals, followed by a single AdLuciferase (AdL.11D) IVT or PO injection. Mice were killed approximately 24 hours after AdL.11D injection and the eyes were enucleated and stored until assayed. Serum samples were also analyzed to determine whether repeated IVT or PO injections lead to induction of neutralizing antibodies directed against an adenovector delivery system. To determine whether preexisting neutralizing anti-Ad antibodies would block transgene expression, mice were preimmunized with one, two, or three intramuscular (IM) injection(s) of AdNull.11D (1 x 10(9) particle units [pu]). Fourteen days later, when systemic anti-Ad antibody titers were expected to exist, mice were given a single AdL.11D injection (IVT or PO) and killed, and the eyes and serum collected. RESULTS: These studies show that multiple injections at 2-week intervals with adenovectors (IM, IVT, or PO) did not prevent transgene expression in the eye. Moreover, measurement of neutralizing anti-Ad antibody titers revealed that measurable anti-Ad antibody titers in mice did not ablate transgene expression. CONCLUSIONS: These studies suggest that transgene expression after repeated adenovector administration into the eye is feasible and repeated injections, whether given IVT or PO, do not lead to an immediate increase in neutralizing anti-Ad antibody titers. Moreover, preimmunization of mice by systemic exposure to adenovector, does not block transgene expression in the eye. These studies indicate that repeat administration of adenovectors (IVT and PO) into the eye can be considered in designing future clinical trials and that the pre-existence of neutralizing anti-Ad antibodies probably does not mitigate activity.     

Tolerability and pharmacokinetics of intravitreal sirolimus

Abstract Purpose: To evaluate the pharmacokinetics (PK) and tolerability of a proprietary sirolimus depot-forming ocular formulation in rabbits and humans after a single intravitreal (IVT) injection. Methods: New Zealand White (NZW) rabbits were intravitreally injected in both eyes with an injectable formulation in 5 (3 PK and 2 tolerability) studies. The rabbits received up to approximately 220?μg sirolimus per eye. At the desired timing post-injection, the animals were euthanized; both eyes were enucleated, frozen, and dissected to separate sclera, retina/choroid, and vitreous humor (VH). Whole blood (WB) samples were obtained at each time point before euthanasia. In clinical trials, patients received an IVT injection of approximately 352?μg sirolimus. Sirolimus concentrations in ocular tissues and WB samples were measured using liquid chromatography/tandem mass spectrometry (LC/MS/MS). In both single- and repeat-dose tolerability studies, systemic and ocular adverse effects were evaluated. Results: After IVT administration, sirolimus formed a depot in the VH. During dissolution, concentrations in VH were dose related and exhibited continuous release from the depot. This was characterized by a gradient of sirolimus concentration in the order of VH > retina/choroid > sclera > WB, and the concentrations were maintained for approximately 2 months after the IVT injection. After repeat dosing (132?μg), no drug accumulation was seen in the ocular tissue or systemically. In clinical studies, the highest blood levels were <2?ng/mL at day 2, and half-time (t(1/2)) was 8-9 days. There was no accumulation at day 30 after the IVT injection (up to 352?μg). Safety studies conducted on rabbits indicated good local tolerability. Sirolimus-related effects were limited to minor incipient cataract findings and mild lenticular changes. In the clinical studies where sirolimus was intravitreally administered up to 352?μg, injections were well tolerated. Conclusions: Sustained IVT delivery was achieved in a dose-dependent fashion after the IVT injection of a proprietary sirolimus depot-forming ocular formulation. Across the tolerability and safety studies, no significant findings were observed for systemic and ocular tolerability. The human WB levels were well below the daily trough systemic blood level range required for systemic immunosuppression. An IVT injection of sirolimus has a PK and safety profile that is favorable for treating inflammatory conditions of the eye, such as non-infectious uveitis, and warrants further investigation in humans.     

Pharmacokinetics of intraocular drug delivery by periocular injections using ocular fluorophotometry

PURPOSE: To evaluate the pharmacokinetics of the periocular injections: posterior subtenon (PST), retrobulbar (RB), and subconjunctival (SC) injection. METHODS: Two sodium fluorescein (NaF) concentrations, 2.5 mg in 0.1 mL (NaF1) and 2.5 mg in 0.5 mL (NaF2) were injected into live rabbits by the PST (NaF1 n = 4, NaF2 n = 3), RB (NaF1 n = 10), SC (NaF1 n = 6), and intravenous (IV, NaF1 n = 6) routes and into euthanatized rabbits by the RB (NaF1 n = 8) route. NaF concentrations in the choroid/retina, vitreous, and anterior segment were measured by ocular fluorophotometry. The NaF level in the contralateral choroid/retina was used as a measure of the systemic drug levels. RESULTS: The maximum NaF concentrations (nanograms per milliliter) in the choroid/retina after PST, RB, SC, and IV were 757 +/- 549 at 2 hours, 906 +/- 1014 at 1 hour, 320 +/- 462 at 2 hours, and 865 +/- 363 at 5 to 10 minutes, respectively. The PST had the highest and most prolonged vitreous NaF1 concentration (maximum: 270 +/- 226 ng/mL at 3.5 hours). The contralateral peak choroid/retina NaF levels after the RB, SC, and IV injections were 7, 4, and 21 times greater than after the PST injection. The SC injection had the highest anterior segment NaF concentration (5364 +/- 2840 ng/mL at 2 hours). PST with NaF2 resulted in intraocular NaF levels higher than with NaF1. CONCLUSIONS: NaF reaches the choroid/retina by transscleral diffusion from the periocular depot. The orbital and conjunctival vasculature and lymphatics have a larger role in NaF clearance than does the choroid. NaF diffuses into the vitreous from the choroid and the anterior segment; the periocular depot location determines the predominant diffusion pathway. The duration of high NaF levels in the choroid/retina or the anterior segment determines vitreous NaF levels. PST is the best periocular route for vitreous NaF delivery with minimal systemic levels. Increasing the volume of NaF PST depot enhances transscleral drug delivery.     

Visual perceptions induced by intravitreous injections of therapeutic agents

Purpose

The purpose of this study was to conduct a questionnaire-based survey of subjective visual perceptions induced by intravitreous (IVT) injections of therapeutic agents.

Patients and methods

Patients undergoing an IVT injection of ranibizumab, pegaptanib sodium, or triamcinolone acetonide were administered a questionnaire in the immediate post-injection period and at 2 weeks of follow-up.

Results

In the immediate post-injection period (75 IVT injections, 75 eyes, 75 patients), lights and floaters were reported after 20 (27%) and 24 (32%) IVT injections, respectively. In comparison, at the 2-week follow-up, the incidence of reported lights (11; 15%) was similar (P>0.05), but the incidence of reported floaters was higher (48; 64% P=0.00). Subgroup analysis for various injection subgroups (no previous injection vsprevious injection(s) in the study eye; injections in study eyes with good VA (logarithm of minimal angle of resolution [logMAR] ≤0.3) vsmoderate VA (0.7 0.3) vspoor VA (logMAR ≥0.7); injections according to pharmacological agent (ranibizumab vspegaptanib vstriamcinolone acetonide); injections in study eyes with choroidal neovascularization (of various causes) vsstudy eyes with macular edema (of various causes); and injections in phakic vspseudophakic eyes) did not reveal any statistically significant associations. Visual perceptions experienced following 15% of IVT injections gave cause for concern to the patient (mean visual analog scale score (±SD): 4.5 (±1.7)), and in 64% of cases, the patients believed that preoperative counseling would have averted the concern.

Conclusions

Lights and floaters are frequent visual perceptions following IVT injections of therapeutic agents. They can give rise to concern that could be alleviated with preinjection counseling.     

Intravitreal bevacizumab alone or combined with 1 mg triamcinolone in diabetic macular edema: a randomized clinical trial

Purpose

To compare the results of intravitreal bevacizumab (IVB) injection alone or in combination with intravitreal 1 mg triamcinolone acetonide (IVT) in center-involved diabetic macular edema.

Methods

In this randomized clinical trial study, ninety-two eyes of 46 patients with bilateral center-involved diabetic macular edema and no previous treatment were included in the study. One eye of each patient was randomly assigned to 1.25 mg of IVB injection or combination of 1.25 IVB and 1 mg IVT. Evaluation of best-corrected visual acuity (BCVA), central macular thickness (CMT), intraocular pressure (IOP) and grading of lens opacity was conducted at baseline, and weeks 2, 4, 6, 8, 12 and 24 after treatment. Retreatment was performed at a 6-week interval whenever indicated based on CMT.

Results

Between the groups, BCVA changes were not statistically different until 24-week follow-up (P > 0.05), but at 24 weeks after treatment, BCVA improvement was significantly better in IVB group (P = 0.049). Significant CMT reduction was observed in each group along the follow-up period (P = 0.001). The mean CMT reduction was more significant in combination (IVB + IVT) group at 2 weeks of follow-up (P < 0.001), but CMT changes were not significant between the groups at weeks 12th and 24th after injection. Overall, retreatment was applied for 59 eyes up to 24 weeks (33 in the IVB group, 26 in the IVB + IVT group). Among patients with 2 or more injections, number of injections was significantly lower in IVB + IVT group (P = 0.043). Three eyes within IVB + IVT group developed IOP rise beyond 21 mmHg, which were controlled with topical anti-glaucoma medications within 1 week. Changes in lens opacity were not significant between two groups.

Conclusion

Eyes treated with IVB plus 1 mg IVT injections had more significant reduction in CMT in early post-injection, but this effect was transient. Although after 24 weeks visual acuity improvement was better in IVB group, combination therapy may decrease the number of injections. Combining 1 mg of intravitreal triamcinolone with bevacizumab was not accompanied with significant side effects.

     

Phase 1 dose-escalation study of a siRNA targeting the RTP801 gene in age-related macular degeneration patients

Background

To evaluate the safety, tolerability, pharmacokinetics, and dose-limiting toxicities of a single intravitreal (IVT) injection of PF-04523655, a 19-nucleotide, O-methyl stabilized, double-stranded small interfering ribonucleic acid targeting the RTP801 gene in patients with neovascular age-related macular degeneration (AMD).

Methods

Prospective, phase 1, clinical multicentre trial, enrolled 27 patients with neovascular AMD unresponsive to prior treatment and best corrected visual acuity (BCVA) ≤20/200 in the study eye in stratum 1: (dose-escalating, open-label: 50 to 3000 μg of PF-04523655) and 27 patients who had potential to benefit from therapy and BCVA of ≤20/100 and ≥20/800 in stratum 2 (parallel, masked study of 1000, 1500, 2250, and 3000 μg of PF-04523655). The primary outcome was safety and tolerability assessment as well as pharmacokinetic profiling following a single IVT injection of PF-04523655.

Results

Doses of PF-04523655 ≥400 μg were generally detectable in the plasma at 1, 4, and 24 h post-injection. And all doses were below the lowest level of quantification by day 14. A single IVT injection of 50 to 3000 μg of PF-045237655 was generally safe and well tolerated over 24 months. There were no dose-limiting toxicities.

Conclusion

A single IVT injection of PF-0523655 ≤3000 μg seems safe and well tolerated in eyes with neovascular AMD.     

Pharmacokinetics of a long-lasting anti-VEGF fusion protein in rabbit

Conbercept(KH902), a recombinant fusion protein in clinical trial II/III, shows good potential to treat the neovascular age-related macular degeneration (AMD). This investigation evaluated its ocular pharmacokinetics and pharmacodynamic profile in rabbits following intravitreal administration (IVT). Rabbits (n = 120) received single bilateral conbercept IVT administration or single IV administration. Conbercept concentrations in ocular tissues and serum were measured after dosing. VEGF concentration was also measured simultaneously. The results showed that conbercept rapidly distributed from vitreous into targeted tissues and lasted over 81 days. Clearance in ocular tissues was parallel and exhibited a terminal half of 2.5-4.2 days. The drug exposure in the retina was 1/4 to 1/5 of that in vitreous. Serum conbercept concentrations after IVT dosing were low and bioavailability was approximately 44%. And single intravitreal injection induced that ocular VEGF concentration declined over 60 days and serum VEGF concentration decreased for a short time but rebounded to higher level than baseline later. All these indicated conbercept good pharmacokinetic profile in rabbits, with good ocular tropism and systemic tolerance. Combined with the efficacy data from our earlier in vitro and in vivo studies, it should have a promising clinical application for AMD treatment.     

Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebo-controlled,randomized clinical trial

Purpose To evaluate the effect of three intravitreal injections of bevacizumab (IVB) alone or combined with triamcinolone (IVT) in the first injection for treatment of refractory diabetic macular edema (DME). Methods In this prospective, placebo-controlled, randomized clinical trial, 115 eyes of 101 patients with refractory DME were included. Subjects were randomly assigned to one of the three study arms: 1) three injections of IVB (1.25 mg/0.05 ml) at 6-week intervals, 2) combined IVB and IVT (1.25 mg/0.05 ml and 2 mg/0.05 ml respectively) followed by two injections of IVB at 6-week intervals, and 3) sham injection (control group). The primary outcome measure was change in central macular thickness (CMT). Secondary outcome measures were change in best-corrected logMAR visual acuity (BCVA ) and incidence of potential adverse events. Results Central macular thickness was reduced significantly in both the IVB and IVB/IVT groups. At week 24, CMT change compared to the baseline was −95.7 μm (95% CI, −172.2 to −19.26) in the IVB group, −92.1 μm (95% CI, −154.4 to −29.7) in the IVB/IVT group, and 34.9 μm (95% CI, 7.9 to 61.9) in the control group. There was a significant difference between the IVB and control groups (P = 0.012) and between the IVB/IVT and control groups (P = 0.022). Improvement of BCVA was initiated at weeks 6 and 12 in the IVB/IVT and IVB groups respectively. In terms of BCVA change compared to the baseline at 24 weeks, the differences between the IVB and control groups (P = 0.01) and also between the IVB/IVT and control groups (P = 0.006) were significant. No significant differences were detected in the changes of CMT and BCVA between the IVB and IVB/IVT groups (P = 0.99). Anterior chamber reaction was noticed in eight (19.5%) and seven (18.9%) eyes respectively in the IVB and IVB/IVT groups the day after injection, and it resolved with no sequel. Elevation of IOP occurred in three eyes (8.1%) in the IVB/IVT group. Conclusion Three consecutive intravitreal injections of bevacizumab had a beneficial effect on refractory DME in terms of CMT reduction and BCVA improvement. Addition of triamcinolone in the first injection seemed to induce earlier visual improvement; however, it did not show any significant additive effect later during follow-up. The 6-week result of this study was presented as a paper at the Annual Meeting of American Academy of Ophthalmology, November 2006, Las Vegas, NV, USA. The authors have no proprietary interest in this study. The authors have full control of all primary data, and they agree to allow Graefe’s Archive for Clinical and Experimental Ophthalmology to review their data upon request. Clinical Trial registration reference number: NCT00370422 (ClinicalTrials.gov).     

Effect of the enzyme inhibitor, phenylmethylsulfonyl fluoride, on the IOP profiles of topical anandamides

PURPOSE: Earlier studies have suggested that the intraocular pressure (IOP) effects of topical arachidonylethanolamide (AEA) are mediated through its fatty acid metabolite, rather than through AEA, per se. The purpose of this study was to investigate whether the topical anandamides AEA and arachidonyl propionitrileamide (APN) decrease IOP when their enzymatic degradation is prevented by phenylmethylsulfonyl fluoride (PMSF) and whether the neuronal cannabinoid (CB1) receptor mediates the IOP responses of an undegraded AEA, through the use of its specific antagonist SR141716A. METHODS: AEA or APN were each formulated in aqueous 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) solutions and administered unilaterally to the rabbit eye (dose, 62.5 microg per rabbit). To prevent the degradation of AEA or APN, the rabbits were pretreated with a subcutaneous (SC) PMSF injection (0.22-22 mg/kg) 30 minutes before eye drop instillation. To determine whether the neuronal cannabinoid (CB1) receptor mediates the hypotensive IOP effects of undegraded AEA, the rabbits were pretreated with simultaneous SC injections of a CB1 receptor antagonist SR141716A (1.2-2.1 mg/kg) and PMSF (2.2 mg/kg) before the ocularly applied AEA. RESULTS: In the absence of PMSF, the IOP profiles of AEA and APN showed a biphasic ocular effect--that is, an initial increase of IOP followed by IOP hypotension in the treated eye. In the presence of PMSF (2.2 mg/kg for AEA and 22 mg/kg for APN), IOP profiles showed immediate IOP reduction in the treated eye. SR141716A antagonized the IOP reduction caused by the undegraded AEA. CONCLUSIONS: These results indicate that the apparently undegraded AEA and APN decrease IOP in normotensive rabbits. AEA-induced IOP reduction in the presence of PMSF is probably mediated through a CB1 receptor.     

Three intravitreal bevacizumab versus two intravitreal triamcinolone injections in recent-onset branch retinal vein occlusion

Purpose

To evaluate the effects of repeated intravitreal injections of bevacizumab (IVB) versus triamcinolone acetonide (IVT) in the treatment of acute branch retinal vein occlusion (BRVO).

Methods

In this randomized clinical trial, 86 eyes with recent-onset (less than 12?weeks) BRVO were included. Participants were randomly assigned to two treatment groups: (1) IVB group (43 eyes), patients who received three monthly injections of 1.25?mg of IVB, and (2) IVT group (43 eyes), patients who received two injections of 2?mg IVT 2?months apart. Patients were examined at 1, 2, 3, 4, and 6?months after enrollment. Main outcome measure was change in best-corrected visual acuity (BCVA) at 6?months. Secondary outcome measures were central macular thickness (CMT) and intraocular pressure (IOP) changes at month 6.

Results

Mean BCVA improved significantly up to 6?months in both groups from 0.68?±?0.25 to 0.31?±?0.21 logMAR (logarithm of minimum angle of resolution) in the IVB group, and from 0.67?±?0.29 to 0.46?±?0.31 logMAR in the IVT group (P?P?=?0.013) and 6 (P?P?=?0.031) at final visit. Dividing the cases into ischemic and non-ischemic types, a significant difference was noted only in the ischemic cases regarding BCVA improvement and CMT reduction in favor of the IVB group. Mean IOP rise was significantly higher in the IVT group at all visits.

Conclusions

Both 3-times-monthly IVB injections and 2-times IVT injections with a 2-month interval could be effective for improving BCVA and CMT in cases with recent-onset BRVO up to 6?months. However, considering the better visual and anatomic outcomes after IVB injections and the potential complications of IVT injections, we would recommend prescheduled repeated IVB injections for such cases. The favorable responses were more pronounced in the ischemic types of BRVO in this trial; nevertheless, this should be confirmed in larger studies.     

Marijuana-derived material-induced changes in monkey ciliary processes differ from those in rabbit ciliary processes

The morphologic changes in ciliary processes and the associated intraocular pressure (IOP) were observed in owl and squirrel monkeys after intravitreal (IVT) and intravenous (IV) injections of water soluble marijuana-derived material (MDM). The response in monkeys differed from that reported in rabbits wherein IV injection induced severe ciliary swelling and a significant decrease in IOP. Only moderate swelling occurs in monkey processes after IV injection of relatively high dose of MDM, and this change, which includes disruption of the basal lamina of the pigment epithelium, is not associated with a change in IOP. Severe swelling occurs in the crests of monkey ciliary processes after IVT injection, which is accompanied by a fall in IOP. The difference in the response in monkey versus rabbit ciliary processes after IV injection of MDM may be due to a more compact stroma in the monkey processes.     

Treatment of vomiting after paediatric strabismus surgery with granisetron,droperidol, and metoclopramide

We have compared the efficacy and safety of granisetron, droperidol, and metoclopramide in the treatment of postoperative vomiting (POV) in children scheduled for strabismus surgery. After experiencing POV during the first 3 h after recovery from anaesthesia, 120 patients received intravenously, in a randomized, double-blind manner, granisetron 40 microg/kg, droperidol 50 microg/kg, or metoclopramide 0.25 mg/kg (n = 40 in each group). The patients were then observed for 24 h after administering the study drugs. Emesis-free episodes were more often observed in patients who had received granisetron (88%) than in those who had received droperidol (63%) or metoclopramide (58%; p < 0.05). No clinically serious adverse events were observed in any group. In conclusion, granisetron is more effective than droperidol or metoclopramide in the treatment of POV after paediatric strabismus surgery.     

Local methotrexate and dexamethasone phosphate for the treatment of recurrent primary intraocular lymphoma

A 70-year-old patient with recurrent bilateral primary intraocular lymphoma (PIOL) was treated with local injections of methotrexate and periocular dexamethasone phosphate to both eyes over the course of 5 months. Local therapy consisted of a cycle to each eye of 3 intravitreal injections of methotrexate (200 microg in a total volume of 0.1 cc) administered on days 1, 5, and 8, followed by a subtenon injection of dexamethasone phosphate (7.5 mg in a total volume of 0.3 cc) on day 9. This treatment cycle was administered 4 times for the right eye and 3 times for the left eye, at 4 to 6 week intervals. Electroretinography was used to assess retinal function prior to and during each treatment regimen. Complete regression of the lymphomatous infiltrates and resolution of the vitritis was observed with preservation of visual acuity and no changes on electroretinography. The effect was sustained for 24 months after termination of treatment in the absence of systemic chemotherapy, radiation treatments, or maintenance intravitreal injections. Local combined chemotherapy can be used to treat recurrent PIOL, and can serve as successful palliative therapy in patients for whom further treatment with systemic chemotherapy or radiation is contraindicated.     

Collagen shields as a drug delivery system for the fourth-generation fluoroquinolones

PURPOSE: To evaluate the penetration of commercially available gatifloxacin and moxifloxacin into the anterior chamber of a rabbit eye using collagen shields presoaked in the antibiotics as a drug delivery system. METHODS: Collagen shields, presoaked for 10 min in commercially available solutions of gatifloxacin (diluted intravenous Tequin) or moxifloxacin (Vigamox) with the same concentration, were placed on the surface of each of the corneas of 12 rabbits for a total of 24 eyes (12 in each group). Aqueous humor samples were taken 3 and 6 h later. RESULTS: The concentrations of both antibiotics were high after 3 h (3.1 +/- 1.3 microg/ml for moxifloxacin and 2.3 +/- 0.8 microg/ml for gatifloxacin, p = 0.22). The concentration of gatifloxacin after 6 h was statistically significantly higher than for moxifloxacin (0.76 +/- 0.33 microg/ml vs. 0.29 + 0.14 microg/ml, respectively, p = 0.03). CONCLUSION: Our results suggest that collagen shields can be effective as a drug delivery system for the fourth-generation fluoroquinolones with a longer effect for gatifloxacin.     

Risks of intravitreous injection: a comprehensive review

PURPOSE: To evaluate the prevalence of the most common serious adverse events associated with intravitreous (IVT) injection. METHODS: A systematic search of the literature via PubMed from 1966 to March 1, 2004, was conducted to identify studies evaluating the safety of IVT injection. Data submitted in New Drug Applications to the U.S. Food and Drug Administration for drugs administered into the vitreous were included where available. Serious adverse events reported in each study were recorded, and risk per eye and risk per injection were calculated for the following serious adverse events: endophthalmitis, retinal detachment, iritis/uveitis, intraocular hemorrhage, ocular hypertension, cataract, and hypotony. Rare complications also were noted. RESULTS: Data from 14,866 IVT injections in 4,382 eyes were analyzed. There were 38 cases of endophthalmitis (including those reported as pseudoendophthalmitis) for a prevalence of 0.3% per injection and 0.9% per eye. Excluding cases reported specifically as pseudoendophthalmitis, the prevalence of endophthalmitis was 0.2% per injection and 0.5% per eye. Retinal detachment, iritis/uveitis, ocular hypertension, cataract, intraocular hemorrhage, and hypotony were generally associated with IVT injection of specific compounds and were infrequently attributed by the investigators to the injection procedure itself. Retinal vascular occlusions were described rarely in patients after IVT injection, and it was unclear in most cases whether these represented true injection-related complications or chance associations. CONCLUSION: The risk of serious adverse events reported after IVT injection is low. Nevertheless, careful attention to injection technique and appropriate postinjection monitoring are essential because uncommon injection-related complications may be associated with permanent vision loss.     

Comparison of the effects of intravitreal bevacizumab and triamcinolone acetonide in the treatment of macular edema secondary to central retinal vein occlusion

Aim:

To compare the effects of intravitrealbevacizumab (IVB) and intravitreal triamcinolone acetonide (IVT) in the treatment of macular edema (ME) secondary to central retinal vein occlusion (CRVO).

Materials and Methods:

There were 20 patients treated with IVB (1.25 mg/0.05 mL) and 16 treated with IVT (4 mg/0.1 mL). The two groups were compared with regard to best-corrected visual acuity (BCVA), central macular thickness (CMT) on optical coherence tomography (OCT), slit-lamp biomicroscopy and fundus fluorescein angiography results, intraocular pressure (IOP), numbers of injections, and adverse events.

Results:

The mean follow-up times in the IVB and IVT groups were 17.45±8.1 months (range: 8–33 months) and 19.94±10.59 months (range: 6–40 months), respectively (P = 0.431). Visual acuity increased and CMT decreased significantly within both groups, but no differences were observed between the groups (P = 0.718). The percentages of patients with increased IOP and iatrogenic cataracts were significantly higher in the IVT group than in the IVB group.

Conclusions:

Treatment with IVB and IVT both resulted in significant improvement in visual acuity and a decrease in CMT in patients with ME secondary to non-ischemic CRVO, with no difference between the two treatments. The incidence of adverse events, however, was significantly greater in the IVT group than in the IVB group. IVB may be preferred over IVT for the treatment of ME in patients with non-ischemic CRVO.     

Postoperative endophthalmitis incidence after intravitreal therapy: a comparison of two different preoperative antibiotic prophylaxis

Prevention of postoperative endophthalmitis (POE) is a goal of every ophthalmic procedure and also in intravitreal therapy (IVT). This comparative retrospective study targets whether systemic and topical preoperative antibiotic prophylaxis (PAP) regimen does prevent POE after IVT in a higher rate compared with topical PAP alone. Out of 6111 IVT performed over a period of 103.5 months, in the study group A patients were treated with systemic and topical PAP (2881 IVT), and in the study group B patients were treated only with topical PAP (3230 IVT). Intravitreal drugs were anti-VEGF, triamcinolone and dexamethasone implants. The incidence of POE in group A (1/2881 or 0.035 % per injection) was not significantly different (P = 0.4) from that in suite B (1/3230 or 0.031 % per injection). Our study states that systemic PAP does not modify the risk of postoperative endophthalmitis in patients treated with IVT.     

Long‐term results of the effect of intravitreal ranibizumab on the retinal arteriolar diameter in patients with neovascular age‐related macular degeneration

Purpose: To study the effect of intravitreal (IVT) ranibizumab on the retinal arteriolar diameter in patients with neovascular age‐related macular degeneration (AMD). Methods: Ten eyes of 10 patients with previously untreated neovascular AMD were included. All eyes had three monthly IVT injections of ranibizumab and then were retreated as needed, based on visual acuity and optical coherence tomography (OCT) criteria. The diameter of the retinal arterioles was measured in vivo with a retinal vessel analyser (RVA) before the first IVT injection, 7 and 30 days after the first, the second and the third injection, and at month 12 of follow‐up. Results: A significant vasoconstriction of the retinal arterioles was observed following each one of the first three IVT injections of ranibizumab. Thirty days following the first, second and third injection, there was a mean decrease of 8.4 ± 3.2%, 11.9 ± 4.5% and 18.5 ± 7.2%, respectively, of the retinal arteriolar diameter compared with baseline (p < 0.01). At month 12, the vasoconstriction was still present with a mean decrease of 19.1 ± 8.3% of the retinal arteriolar diameter compared with baseline (p < 0.01). Median number of ranibizumab injections was 4 (range 3–10). There was no correlation between the number of injections and percentage diameter decrease at month 12 (r = ?0.54, p > 0.1). There was no significant change in mean arterial pressure (MAP) during the period of follow‐up (p > 0.05). Conclusions: These results suggest that IVT ranibizumab induces sustained retinal arteriolar vasoconstriction in eyes with neovascular AMD.     

Twenty-Four Months Follow-Up of Intravitreal Bevacizumab Injection Versus Intravitreal Triamcinolone Acetonide Injection for the Management of Persistent Non-Infectious Uveitic Cystoid Macular Edema

Purpose: To report the efficacy of intravitreal bevacizumab (IVB) injection versus intravitreal triamcinolone acetonide (IVT) for persistent non-infectious uveitic cystoid macular edema (CME).

Methods: Interventional retrospective comparative case series evaluated 37 consecutive patients (44 eyes) with completely controlled uveitis and recalcitrant CME. Patients received repeated injections of 1.25 mg of IVB or 4 mg of IVT.

Results: Best-corrected visual acuity (BCVA) at baseline and 24 months was logMAR 1 and 0.8 respectively, in the IVB group (p = 0.002) and; logMAR of 1.1 and 0.6, in the IVT group (p = 0.001). Central macular thickness at baseline and 24 months was 399.2 µm and 333.7 µm (p < 0.0009), respectively, for the IVB group and; 464.4 µm and 316.5 µm in the IVT group (p = 0.044). Postoperatively, IOP increased in the IVT group.

Conclusions: Repeated injections with IVT improve BCVA as effectively as repeated injections with IVB in the long-term management of persistent uveitic CME.     

FK506及其纳米粒的房水药代动力学的实验研究

目的探讨FK506及其纳米粒的房水药代动力学特征。方法42只新西兰白兔分为:(1)FK506纳米胶体液滴眼组(18只兔)和注射组(16只兔):双眼结膜囊滴入或结膜下注射10μgFK506的纳米胶体溶液;(2)不含纳米微粒的FK506滴眼组(8只兔):再分为2个亚组,即双眼结膜囊分别滴入20μg和40μg FK506的滴眼液。不同时间点采集房水,酶联免疫法测定房水中FK506含量,计算药代动力学参数。结果含10μg FK506的纳米胶体溶液结膜下注射和滴眼后房水有效药物浓度可分别维持96 h和16 h;结膜下注射后2 h房水浓度为(1.15±0.25)ng/m、l6~96 h房水浓度为(9.62±2.19)~(2.60±0.21)ng/m l,滴眼16 h内房水浓度为(15.50±3.39)~(2.59±0.83)ng/m l;药代动力学参数分别为:达峰时间(Tm ax)(64.00±13.86)h和(1.25±0.50)h,达峰浓度(Cm ax)(10.16±1.37)ng/m l和(15.52±2.37)ng/m l,曲线下面积(AUC0→t)(612.48±54.39)ng.m l-1.h-1和(152.44±16.74)ng.m l-1.h-1,吸收速率常数(Ka)0.040±0.004和3.790±0.730,平均滞留时间(MRT)(58.53±5.42)h和(8.20±1.28)h。房水中FK506质量浓度呈一室模型。不含纳米微粒的FK506(20μg和40μg)液滴眼后房水有效药物浓度维持均≤4 h;其中含20μgFK506液的Tm ax为1 h,Cm ax为(18.93±6.95)ng/m l;含40μg FK506液的Tm ax为2 h;Cm ax为(28.33±1.31)ng/m。l结论采用FK506纳米粒胶体溶液行结膜下注射和滴眼时均可延长FK506药物在房水中的滞留时间,而且结膜下注射能使房水中维持的有效药物浓度相对较低和时间更长