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Diabetic Macular Oedema


compared with the laser alone group at all study follow-up visits. An improvement of two or more Early Treatment Diabetic Retinopathy Study (ETDRS) lines was observed in 63.1 % and 10.5 % of eyes, respectively (p<0.001). A significant decrease in mean central macular thickness occurred in the TA and laser group when compared with the laser alone group at all study follow-up intervals (p<0.001). At 12 months, mean (±SD) reductions in central macular thickness were 123 ± 68 μm and 65 ± 51 μm, respectively (p<0.001).37


Several


other studies reported favourable results of intravitreal TA in refractory DMO.23,38–40


In a six-month prospective, placebo-controlled,


randomised clinical trial conducted by Jonas et al., 40 eyes with persistent DMO were enrolled and randomised to treatment with 20 mg TA (n=28) or to placebo injection (n=12). Visual acuity increased significantly (p<0.001) in the TA group by 3.4 ETDRS lines. In the placebo group, visual acuity did not change significantly (p=0.07) during the six months. At the end of follow-up period, 48 % in the TA group improved by at least two ETDRS lines compared with 0 % eyes in the placebo group.23


Recently, Gillies et al. reported the


longest-term data available concerning the outcomes of intravitreal injection of TA. This was a five-year prospective, double-masked, randomised clinical trial of 4 mg dose of preservative-free intravitreal TA in comparison with placebo. In this study, 67 study eyes with refractory DMO were randomised to receive 4 mg TA (n=33) or placebo (n=34). At five years, an improvement in visual acuity of three or more lines occurred in 42 % of eyes in the TA group and 32 % of eyes in the placebo group (p=0.4). A worsening of visual acuity by three or more lines occurred in 18 % and 24 % of eyes, respectively (p=0.88). Mean (±SD) reductions in central macular thickness were 100 ± 79 μm in the TA group and 184 ± 29 μm in the placebo group (p=0.45). After five years the difference in visual acuity between the two groups was not statistically significant and there was no difference in mean central macular thickness reduction between two groups.39 Moreover, this study showed that, in the long term, a two-year delay in the beginning of intravitreal TA treatment did not seem to adversely affect outcomes in eyes affected with refractory DMO.


Dosage


The appropriate dose of intravitreal TA remains a subject of debate. Both Hauser et al. and Audren et al. showed that the use of a 4 mg dose of intravitreal TA does not have enough advantages over the lower 1 mg or 2 mg dose.40,41


However, Lam et al. published a


By using a dose of about 20 mg of TA, the increase in visual acuity was most marked during the first three and six months after injection and was observable for a period of about six to nine months. Differently, by using a dose of 4 mg, the duration in the reduction of macular thickness as measured by optical coherence tomography (OCT) was less than six months.43


comparison between 4 mg and 8 mg doses and showed that the higher dose had a more sustained effect on both visual acuity and central macular thickness, although with a trend to more ocular complications.42


Other Routes of Administration


While intravitreal TA administration has been shown useful to reduce the macular oedema and to improve or at least stabilise visual acuity, these effects are often transient and associated with several adverse events. Therefore, emerging pharmacological approaches are being evaluated for the treatment of DMO, including extraocular delivery routes and intravitreal steroid-releasing implants. Geroski et al. reported that therapeutic doses of TA could reach the posterior segment via transscleral absorption with periocular administration.44


44


Thus, other routes of TA administration, such as sub-conjunctival, sub-Tenon and posterior juxtascleral infusions, have been considered. The commonly reported advantages of periocular administration of TA versus intravitreal injection include a lower risk of IOP elevation and endophthalmitis. However, peribulbar injections of TA seem to result in lower morphological and functional outcomes as compared with those reported with the use of intravitreal TA.45–50


Recently, a 12-month


interventional case report demonstrated that posterior juxtascleral infusion of a viscoelastic formulation of TA is an effective treatment for diffuse DMO unresponsive to laser photocoagulation.51


Morphological


results indicated that macular thickness changed significantly (p<0.001) after 12 months of follow-up. Serial comparison between baseline and post-treatment values demonstrated that the decrease in the mean central foveal thickness (CFT) was significant at each follow-up time (p<0.0005). One week after TA infusion, mean reduction in CFT was 134 µm and the effect duration reaches approximately six–nine months. One infusion only was given in 54.5 % of eyes. A decrease in macular thickening of 50 % or more was present in half of the eyes at the end of the 12 months of follow-up. Moreover, BCVA results changed significantly (p<0.006). Serial comparison between baseline and post-treatment values demonstrated that the improvement in mean BCVA was significant one, three, nine and 12 months after treatment (p<0.008). At the end of the study, the mean improvement in BCVA was 0.15 logMAR. In 63 % of eyes, the improvement was at least one ETDRS line, and in 27.3 % cases it was greater than three ETDRS lines. A BCVA reduction of more than three lines was noted in four cases during the follow-up time.


To provide long-term drug delivery to the macular region and to limit the frequency of repeated intraocular TA injections, several intravitreal steroid-releasing therapies are being proposed for the treatment of DMO. A controlled-release microsphere system for TA has been recently reported. A single intravitreal injection of 1 mg TA in a controlled-release poly(lactide-co-glycolide) (PLGA) microsphere system (intravitreal bioerudivel sustained-release triamcinolone microspheres system; RETAAC system) has been compared with a single intravitreal injection of 4 mg TA in patients with DMO unresponsive to laser photocoagulation. Both the safety and the anatomic and functional outcomes were evaluated. RETAAC-treated eyes showed marked decrease of retinal thickness as well as improved visual acuity after 12 months of follow-up. This study demonstrated a superior long-term pharmacologic performance compared with TA-injected eyes. No drug- or procedure-related side effects were observed in this study.52


Another promising approach seems to be


represented by Verisome® technology. Verisome is a sustained-release drug delivery system that can be injected into the eye as a liquid via a standard 30-gauge needle. The biodegradable vehicle provides controlled, extended drug release over a titratable period of up to one year. The liquid-gel formulation was designed to deliver TA for up to one year via a single intravitreal injection to treat patients with macular oedema associated with retinal vein occlusion.53


The results of the


clinical trial confirmed the expected safety and efficacy characteristics and the controlled-release attributes of the technology. Recently, Verisome technology has been proposed to treat patients affected with DMO.54


Moreover, new biodegradable and non-biodegradable steroid delivery systems are being evaluated for long-term efficacy in chronic diseases, such as DMO. These include dexamethasone (Ozurdex®, Allergan Inc., Irvine, CA) and fluocinolone acetonide implants (Iluvien®, Alimera Sciences, Alpharetta, GA), both of which have an approximately five-fold increase in corticosteroid potency.55,56


EUROPEAN ENDOCRINOLOGY


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