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Fluocinolone acetonide sustained drug delivery device to treat severe uveitis
Abstract
Uveitis is often a chronic disease requiring long-term medical therapy. In this report, we describe a pilot safety and efficacy trial of a novel sustained drug delivery system containing fluocinolone acetonide to treat patients with severe uveitis.
Prospective, noncomparative, interventional case series
Patients with severe uveitis.
Sustained drug delivery devices designed to release fluocinolone acetonide for at least 2.5 years were implanted through the pars plana into the vitreous cavity of seven eyes of five patients. All patients had severe uveitis not well controlled with, or intolerant to, repeated periocular corticosteroid injections, systemic corticosteroids, nonsteroidal immunosuppressive agents, or a combination thereof at the time of device implantation. Before device implantation, patients underwent complete evaluation including history, ophthalmologic examination, fluorescein angiography, visual field testing, and electroretinography. After surgery, patients were reexamined at 1 week, 2 weeks, 4 weeks, and at 1- to 3-month intervals. Visual fields, electroretinograms, and fluorescein angiography were repeated at 3- to 6-month intervals.
Preoperative and postoperative visual acuity, ocular inflammation, anti-inflammatory medication use, and intraocular pressure.
Patients had a diagnosis of Behçet's syndrome (two eyes), or idiopathic panuveitis (five eyes, including two with necrotizing retinitis, two with progressive chorioretinitis, and one with iridocyclitis and intermediate uveitis). Patients were observed an average of 10 months (range, 5-19 months). All eyes had stabilized or improved visual acuity after device implantation, and four of seven eyes had an improvement of three lines or more. The mean initial visual acuity, measured by Snellen chart, was 20/207, and the mean final visual acuity was 20/57 (P = 0.02). After surgery, at the final visit, no eye had clinically detectable inflammation, and all seven eyes had a marked reduction in systemic, topical, and periocular anti-inflammatory medication use. Four eyes had increased intraocular pressure 6 weeks to 6 months after device implantation. Intraocular pressure has been controlled on topical medications. No patient experienced intraoperative complications.
A fluocinolone acetonide sustained drug delivery device is a promising new therapy for the treatment of severe uveitis. Intraocular pressure must be carefully monitored long after device implantation. Based on these data, a randomized study of a larger group of patients is warranted.
... It has been shown that these devices are nontoxic and produce constant intraocular drug levels for an extended period in human and experimental models. 73,[90][91][92] Jaffe et al, in a prospective, noncomparative case series of 7 eyes (5 patients) with severe uveitis, implanted non-biodegradable intraocular sustained drug delivery devices containing 2 mg and 15 mg fluocinolone acetonide. After an average of 10 months of follow-up, favorable effects were observed with improvement of intraocular inflammation and consequent marked reduction of anti-inflammatory medication, preservation or improvement of visual acuity, and reversal of CME. 90 However, all eyes underwent cataract extraction at the time of device implantation or shortly thereafter, hence improvement in visual acuity cannot be directly related to the fluocinolone acetonide. ...
... After an average of 10 months of follow-up, favorable effects were observed with improvement of intraocular inflammation and consequent marked reduction of anti-inflammatory medication, preservation or improvement of visual acuity, and reversal of CME. 90 However, all eyes underwent cataract extraction at the time of device implantation or shortly thereafter, hence improvement in visual acuity cannot be directly related to the fluocinolone acetonide. Potential side effects of this treatment modality include rhegmatogenous retinal detachment, vitreous hemorrhage, device extrusion, endophthalmitis, increased intraocular pressure, and suture exposure. ...
... Potential side effects of this treatment modality include rhegmatogenous retinal detachment, vitreous hemorrhage, device extrusion, endophthalmitis, increased intraocular pressure, and suture exposure. 90 Large, randomized, controlled trials are currently underway in the USA, Europe, Asia, and Australia in order to evaluate more effectively their risks and benefits and their long-term follow-up. ...
... The implant was efficacious in preserving visual acuity, and electroretinographic parameters, and improved retinal vascular leakage. The Retisert ® implant was able to effectively treat CMO in 100% of BRC patients at 24 months [28], with clinical outcomes similar to those of other non-infectious posterior uveitis treated with Retisert ® [30]. The researchers reported a very high incidence of cataract progression and glaucoma [28]. ...
... This is because of the lower dose of fluocinolone steroid released by the Iluvien ® implant compared to the Retisert ® . Subsequently, different studies proved the therapeutic efficacy of FAc 0.59mg implants in the management of BRC, affirming the role of such devices in the successful discontinuation of systemic corticosteroids or conventional immunomodulatory therapy [29][30][31]. ...
Purpose
To report treatment outcomes and efficacy of the fluocinolone acetonide 0.19 mg intravitreal implant (Iluvien) in controlling retinal and choroidal inflammation in 11 patients with birdshot retinochoroiditis.
Methods
A single-centre, retrospective, interventional case series. The primary efficacy end point was improvement in vascular leakage on fluorescein angiography (FA), effect on cystoid macular oedema (CMO) and resolution of hypofluorescent lesions on indocyanine green angiography (ICGA); secondary measures were improvements on pattern and full-field electroretinogram (PERG; ERG) parameters. Safety outcome measures were intraocular elevation and cataractogenesis.
Results
Fifteen eyes received Iluvien implant with an average follow-up of 31 months (range 12–36 months). Prior to the implant, 5 (33.3%) eyes had received dexamethasone intravitreal implant 0.7 mg (Ozurdex). FA showed evidence of vascular leakage in all eyes at baseline. Between month 6 and 12, FA showed that 73.4% of eyes had no leakage, this increased to 84.6% by month 24. Three eyes in our study had CMO at baseline. 6 months after Iluvien implant, all eyes achieved complete CMO resolution. One year after insertion of the implant, the characteristic hypofluorescent lesions on ICGA were unchanged in all cases. There was baseline ERG evidence indicating a high incidence of peripheral cone system dysfunction and most showed PERG evidence of macular dysfunction. Retinal function improved and macular function improved or was stable in the majority following treatment.
Conclusions
The results show the possible therapeutic effect of Iluvien in the management of Birdshot-related vascular leakage, CMO and retinal dysfunction. However, choroidal lesions seem to persist with no detectable response to treatment.
... In case of vitrectomized eyes, a pars plana infusion line can be used to prevent chances of globe collapse. [3,5,42] Having a limited lifespan, Retisert may need re-implantation in patients with chronic uveitis to maintain disease quiescence. Such re-implantation may be done with or without exchange of the old implant. ...
... [43] There is a high risk of dissociation of implant during removal/exchange surgery. [44] The prospective, interventional, pilot study conducted by Jaffe et al. [42] in 2000 showed a marked reduction in anti-inflammatory medication use and statistically significant improvement in BCVA following implantation of FA implant in seven eyes of five patients. ...
The management of uveitis is challenging for most treating ophthalmologists. The treatment of uveitis often requires the use of high dose of systemic corticosteroid and immunosuppressive agents, which are almost always associated with potential side effects. Intravitreal medications have become a popular mode of drug administration in uveitis patients as they provide high volume of drug to the target tissues, eliminating the risk of systemic toxicity. There has been tremendous development in the intravitreal therapeutics over the last few years. With the advent of sustained-release technique, increasing patient compliance, biodegradable nature of the implant, and introduction of newer agents with better safety profile, the intravitreal medications have become more popular in recent years. This review presents evidence in the scientific literature supporting the use of intravitreal medications for the management of uveitis and its complications.
... 19,20 Treatment Protocol Clinicians and participants were instructed to apply the assigned treatment strategy throughout the trial; during the follow-up study, they were encouraged to continue the same treatment regimen unless contraindicated. The implant therapy protocol required suppression of anterior chamber inflammation with topical, periocular, and/or systemic corticosteroids, then placement of an intravitreous fluocinolone acetonide implant (0.59 mg) (Bausch & Lomb) by study-certified surgeons using a recommended technique 10,21 within 28 and 56 days after randomization in the first and second (if indicated) eyes, respectively. Thereafter, the protocol required tapering and cessation of systemic corticosteroids, immunosuppressants, or both, with reimplantation on occurrence of reactivated inflammation sufficiently severe to otherwise require systemic therapy. ...
... Although both approaches usually were successful in controlling inflammation, implant therapy achieved inflammatory control both faster and more often during the first 5 years after implantation. Implant therapy sometimes was used to rescue patients whose uveitis did not respond to systemic therapy, as reported elsewhere 10,40 ; implant therapy also controlled uveitis about 50% longer than had been anticipated, suggesting advantages of this approach when systemic therapy fails or is not feasible. After 5 years, uveitis reactivations occurred often enough to make the proportion controlled not significantly different thereafter. ...
Importance:
A randomized clinical trial comparing fluocinolone acetonide implant vs systemic corticosteroids and immunosuppression for treatment of severe noninfectious intermediate, posterior, and panuveitides did not result in a significant difference in visual acuity at 2 and 4.5 years; longer-term outcomes are not known.
Objective:
To compare the association between intravitreous fluocinolone acetonide implant vs systemic therapy and long-term visual and other outcomes in patients with uveitis.
Design, setting, and participants:
Nonprespecified 7-year observational follow-up of the Multicenter Uveitis Steroid Treatment (MUST) randomized clinical trial comparing the alternative treatments. Follow-up was conducted in tertiary uveitis subspecialty practices in the United States (21), the United Kingdom (1), and Australia (1). Of 255 patients 13 years or older with intermediate, posterior, or panuveitis (active within ≤60 days) enrolled in the MUST trial between December 6, 2005, and December 9, 2008, 215 consented to ongoing follow-up through at least 7 years postrandomization (last visit, February 10, 2016).
Interventions:
Participants had been randomized to receive a surgically placed intravitreous fluocinolone acetonide implant or systemic corticosteroids supplemented by immunosuppression. When both eyes required treatment, both eyes were treated.
Main outcomes and measures:
Primary outcome was change from baseline in best-corrected visual acuity in uveitic eyes (5 letters = 1 visual acuity chart line; potential range of change in letters read, -121 to +101; minimal clinically important difference, 7 letters), analyzed by treatment assignment accounting for nonindependence of eyes when patients had 2 uveitic eyes. Secondary outcomes included potential systemic toxicities of corticosteroid and immunosuppressive therapy and death.
Results:
Seven-year data were obtained for 161 uveitic eyes (70% of 90 patients assigned to implant) and 167 uveitic eyes (71% of 90 patients assigned to systemic therapy) (77% female; median age at enrollment, 48 [interquartile range, 36-56] years). Change in mean visual acuity from baseline (implant, 61.7; systemic therapy, 65.0) through 7 years (implant, 55.8; systemic therapy, 66.2) favored systemic therapy by 7.2 (95% CI, 2.1-12) letters. Among protocol-specified, prospectively collected systemic adverse outcomes, the cumulative 7-year incidence in the implant and systemic therapy groups, respectively, was less than 10%, with the exceptions of hyperlipidemia (6.1% vs 11.2%), hypertension (9.8% vs 18.4%), osteopenia (41.5% vs 43.1%), fractures (11.3% vs 18.6%), hospitalization (47.6% vs 42.3%), and antibiotic-treated infection (57.4% vs 72.3%).
Conclusions and relevance:
In 7-year extended follow-up of a randomized trial of patients with severe intermediate, posterior, or panuveitis, those randomized to receive systemic therapy had better visual acuity than those randomized to receive intravitreous fluocinolone acetonide implants. Study interpretation is limited by loss to follow-up.
Trial registration:
clinicaltrials.gov Identifier: NCT00132691.
... Im Lumen des Röhrchens Die Ophthalmologie 3 Übersichten Abb. 2 8 Verlauf eines Panuveitisschubes unter der Behandlung mit DEX-Implantaten wird das FAc in einer Matrix gebunden, das über die semipermeable Polyvinylalkohol-Membran an einem Ende des Implantates freigesetzt wird. Das andere Ende des FAc-Implantats ist nicht permeabel [7,14]. ...
Uveitis leads to blindness in 10–15% of all cases in industrialized nations. The prevalence varies depending on the literature, ranging from 9 to 730 cases per 100,000 inhabitants. Local and systemic steroid applications, along with treatment involving immunomodulators, are the primary treatment options. In cases of chronic and refractory uveitis, especially with the manifestation of uveitic macular edema, intravitreal corticosteroids can contribute to reduce or completely replace systemic immunomodulatory therapy with disease-modifying antirheumatic drugs (DMARDs), biologics or corticosteroids.
This review article presents the currently available intravitreal corticosteroid implants used in the treatment of noninfectious uveitis. The indications, effectiveness, and side effect profiles are discussed within the context of the current literature. A total of 6 randomized controlled studies about FAc and DEX implants with more than 100 patients were included in this review. One subgroup analysis from a multicentric randomized study with 315 patients has been included as well. The outcome is discussed in this article.
The efficacy and safety profile of intravitreal corticosteroids in uveitic macular edema have been evaluated in several studies in recent years. In some studies, they have been compared to systemic treatment options. With long-acting corticosteroid implants the number of relapses can be reduced and the time interval between relapses can be prolonged. Short-acting corticosteroid implants represent a treatment option during acute uveitic activity. The adverse effects of corticosteroids can be well-controlled in most cases. In phakic and/or young patients, however, adverse effects (such as cataract development) should be discussed in depth before treatment initiation as most corticosteroids are applied as long-term treatment.
... The pilot study of the fl uocinolone acetonide implant demonstrated no statistically significant increase in intraocular pressure, but showed that an increased proportion of implanted eyes required pressure-lowering topical medication (Jaffe et al 2000a). Safety evaluation in the follow-up study mirrored these fi ndings, with a statistically insignifi cant increase in intraocular pressure in implanted eyes from 14 mm Hg at baseline to 18.8 mm Hg at 24 months. ...
Uveitis is a potentially sight-threatening inflammatory eye disease caused by multiple infectious and non-infectious etiologies for which the standard of care involves corticosteroids or various immunomodulary therapy (IMT) drugs. These available treatments, although effective, may cause significant morbidity and sometimes mortality in uveitis patients due to their toxic side-effects and the necessity of long-term therapy to prevent recurrences. In order to avoid the systemic toxicity of corticosteroids and IMT or the repeated injections of local steroids necessary to control ocular inflammation, and to prevent development of cumulative damage resulting from recurrent episodes of inflammation, researchers have developed a number of local corticosteroid sustained-release devices that can be implanted directly into the vitreous of the eye, at the site of the inflammatory disease. Preliminary studies of such a device, the fluocinolone acetonide (Retisert™) implant, have shown significant reductions in the number of inflammatory episodes and decreased reliance on systemic corticosteroids or other IMT. This review explores the current research evaluating the fluocinolone sustained-release intravitreal implant in the treatment of posterior uveitis and the implications for its future use on a wider scale.
... Furthermore, it would have been desirable to evaluate the outcome beyond 2 years after FAc implantation as the implant has an effective duration of up to 3 years. 4 As data between 2 and 3 years after FAc implantation were not available for most patients, we chose not to impute the data to avoid the shortcomings associated with imputation. In addition, due to the small sample size, the regression analysis might be underpowered. ...
Purpose
This study investigated the impact of baseline clinical and optical coherence tomography (OCT) factors on the response to a 0.19-mg fluocinolone acetonide (FAc) implant in patients with noninfectious uveitic macular edema evaluated by the area under the curve over 24 months.
Methods
A retrospective study was conducted of eyes of patients with noninfectious uveitic macular edema undergoing FAc treatment, with follow-up from baseline to 24 months. The area under the curve (AUC) of best-corrected visual acuity (BCVA) and the central macular thickness (CMT) were calculated using the trapezoidal rule. Clinical and OCT data at the time of FAc administration were collected, and associations with AUC of BCVA and CMT changes were investigated.
Results
Twenty-three patients were enrolled. BCVA and CMT significantly improved after FAc implantation (P < 0.05). AUCBCVA and AUCCMT were 0.41 ± 0.33 logarithm of minimal angle of resolution/6 months and 320.15 ± 321.64 μm/6 months, respectively. Better baseline BCVA (coefficient [coef.] = 0.83, P < 0.001) and macular thickness reduction after FAc administration (coef. = −0.0001, P < 0.05) were associated with better BCVA after FAc treatment. In contrast, baseline OCT biomarkers such as ellipsoid zone reflectivity and choroidal vascularity index, sex, or disease duration before FAc injection showed no correlation with AUCBCVA and AUCCMT (P > 0.05). The younger the patient at the time of FAc injection, the greater the reduction in CMT (coef. = 1.76, P < 0.05).
Conclusions
Among all clinical and morphological baseline factors, Baseline BCVA was the strongest predictor for AUCBCVA, while no association with baseline OCT features was observed. Overall, improvement of BCVA and CMT after FAc injection was maintained over 24 months.
This study is registered in the German Clinical Trials Register under the DRKS-ID: DRKS00024399.
... Retisert® was approved in the United States in 2005 for treating noninfectious uveitis. Retisert® encapsulates 0.59 mg of fluocinolone acetonide that is stably released over 30 months [28]. Surgery is required for implant removal and replenishing the drug [24]. ...
Effective drug therapy for vitreoretinal disease is a major challenge in the field of ophthalmology; various protective systems, including anatomical and physiological barriers, complicate drug delivery to precise targets. However, as the eye is a closed cavity, it is an ideal target for local administration. Various types of drug delivery systems have been investigated that take advantage of this aspect of the eye, enhancing ocular permeability and optimizing local drug concentrations. Many drugs, mainly anti-VEGF drugs, have been evaluated in clinical trials and have provided clinical benefit to many patients. In the near future, innovative drug delivery systems will be developed to avoid frequent intravitreal administration of drugs and maintain effective drug concentrations for a long period of time. Here, we review the published literature on various drugs and administration routes and current clinical applications. Recent advances in drug delivery systems are discussed along with future prospects.
... Retisert is used to treat chronic noninfectious uveitis but was also effective against diabetes-related edema and central retinal vein occlusion. Reductions in recurrence rates from 62% per year before implantation to 4%, 10% and 20% in the first, second, and third years after implantation, respectively, have been demonstrated [44,46]. ...
Background — Intravitreal implants solve a number of serious problems arising in diseases of the posterior segment of the eyeball. Unlike intravitreal injections, the implant provides a prolonged release of a pharmaceutical drug over time. The review presents the characteristics of existing systems for intravitreal drug delivery: nanosystems, non-biodegradable and biodegradable implants. The review also highlights the main advantages and disadvantages of various implants. Based on the conducted literature review, the following conclusion is formulated: the most promising means of targeted drug delivery of drugs to the posterior segment of the eyeball are biodegradable implants. However, currently existing biodegradable implants do not provide entirely controlled release of the drug (uncontrollable extraction episodes occur at times), which constitutes a serious issue requiring improvement. Objective — to summarize the published data on existing systems for the targeted drug delivery into the vitreous chamber, identifying their major advantages and disadvantages. Material and Methods — Information was searched in such databases as PubMed, Google Scholar and ClinicalTrials.gov, using the keywords in both Russian and English languages: intravitreal implants, intraocular implants, biodegradable implants, non-biodegradable implants, nanosystems, nanoparticles, liposomes, targeted drug delivery, posterior segment of the eye, etc.
... The insert is completely biodegradable [94]. Retisert Ò is non-biodegradable fluocinolone acetonide (0.59 mg) implant surrounded by a polyvinyl acetate/silicone thin layer fixed onto a structural base [95]. Retisert Ò has been reported to reduce recurrence rates of non-infectious uveitis with acceptable tolerability and reduced side effects [96]. ...
Non-oral long-acting drug delivery systems (LADDS) encompass a range of technologies for precisely delivering drug molecules into target tissues either through the systemic circulation or via localized injections for treating chronic diseases like diabetes, cancer, and brain disorders as well as for age-related eye diseases. LADDS have been shown to prolong drug release from 24 hours up to 3 years depending on characteristics of the drug and delivery system. LADDS can offer potentially safer, more effective, and patient friendly treatment options compared to more invasive modes of drug administration such as repeated injections or minor surgical intervention. Whilst there is no single technology or definition that can comprehensively embrace LADDS; for the purposes of this review, these systems include solid implants, inserts, transdermal patches, wafers and in situ forming delivery systems. This review covers common chronic illnesses, where candidate drugs have been incorporated into LADDS, examples of marketed long-acting pharmaceuticals, as well as newly emerging technologies, used in the fabrication of LADDS.
... Fluocinolone is a synthetic fluorinated glucocorticoid ((6a, 11b, 16a)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis-(oxy)]-pregna-1,4-diene-3,20-dione) with low solubility in aqueous. 15,16 A human pharmacokinetic study showed that following a 0.2 μg/day insert, peak drug levels in the aqueous (slightly >2ng/mL) were sustained for approximately 3 months, followed by steady-state levels from around 6 months (0.5-1.0ng/mL) for 36 months. 17 Therefore, a 0.2 μg/day insert provides stable long-term release of FA, the drug then diffusing from vitreous into retina/choroid and other ocular tissues. ...
Long-acting, slow-release injectable fluocinolone intravitreal implants have been approved for the treatment of non-infectious uveitis affecting the posterior segment. We summarise the development of intravitreal fluocinolone implants and discuss the technology including pharmacokinetics. We conducted a systematic review of evidence for the efficacy, safety and patient acceptability of fluocinolone 0.18 mg and 0.19 mg injectable implants. We summarise evidence from the pivotal phase 3 studies that lead to the approval of these implants and evaluate real-world including disease-specific evidence. Safety including injection-related events and long-term adverse events is presented.
... Pharmacokinetics of intravitreally injected Ozurdex® were studied in an animal model. Following bilateral Ozurdex® implantation in 34 male monkeys, the results showed a higher rate of initial drug release during the first 2 months followed by a prolonged low level of release and dexamethasone level was below the limit of detection after 6 months [218]. A more recently approved dexamethasone-based slow-release system is DEXYCU®. ...
... Pharmacokinetics of intravitreally injected Ozurdex® were studied in an animal model. Following bilateral Ozurdex® implantation in 34 male monkeys, the results showed a higher rate of initial drug release during the first 2 months followed by a prolonged low level of release and dexamethasone level was below the limit of detection after 6 months [218]. A more recently approved dexamethasone-based slow-release system is DEXYCU®. ...
Corticosteroids remain the mainstay of the treatment for various ocular conditions affecting the ocular surface, anterior and posterior segments of the eye due to their anti-inflammatory, anti-oedematous, and anti-neovascularization properties. Prednisolone, prednisolone acetate, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, and loteprednol etabonate are amongst the most widely used ophthalmic corticosteroids. Corticosteroids differ in their activity and potency in the eye due to their inherent pharmacological and pharmaceutical differences. Different routes and regimens are available for ocular administration of corticosteroids. Conventional topical application to the eye is the route of choice when targeting diseases affecting the ocular surface and anterior segment, while periocular, intravitreal, and suprachoroidal injections can be potentially effective for posterior segment diseases. Corticosteroid-induced intraocular pressure elevation and cataract formation remain the most significant local risks following topical as well as systemic corticosteroid administration. Invasive drug administration via intracameral, subconjunctival, and intravitreal injection can enhance ocular bioavailability and minimize dose and dosing frequency of administration, yet may exacerbate ocular side effects of corticosteroids. This review provides a critical appraisal of the oph-thalmic uses of corticosteroid, routes of administration, drug delivery fundamentals and novel ocular implantable steroid delivery systems, factors influencing side effects, and future perspectives for ocular corticosteroid therapy.
... To overcome these sustained release intravitreal corticosteroid implants may be considered [21]. Ozurdex Ò [Allergen Pharmaceuticals] is a biodegradable intravitreal implant loaded with 0.7 mg dexamethasone and is placed via pars plana approach [22]. ...
Purpose
To review the current regimens and novel therapeutic modalities in various stages of research and development for the management of non-infectious posterior uveitis (NIPU).
Methods
We performed a thorough review of current literature using PubMed, Google Scholar and Clinicaltrials.gov to identify the published literature about the available therapeutics and novel drugs/therapies in different stages of clinical trials.
Results
The current management regimen for non-infectious posterior uveitis includes corticosteroids, immunomodulatory therapies and anti-metabolites. However, NIPU requires long-term management for efficacious remission of the disease and to prevent disease relapse. Long-term safety issues associated with steroids have led to efforts to develop novel therapeutic agents including biological response modulators and immunosuppressants. The current therapeutic agents in various stages of development include calcineurin inhibitors, biologic response modifiers and a more a comprehensive modalities like ocular gene therapy as well as novel drug delivery mechanisms for higher bioavailability to the target tissues, with minimal systemic effects.
Conclusion
Novel efficacious therapeutic modalities under development will help overcome the challenges associated with the traditional therapeutic agents.
... Due to their "neutral" surface charge and nanoscale size, hydroxylterminated PAMAM dendrimers are noncytotoxic with reduced nonspecific tissue interactions [22,31,32]. Systemic and intravitreal hydroxyl-PAMAM dendrimers are readily cleared intact from off-target organs, but are selectively localized and retained in the areas of inflammation in the brain and retina [33][34][35][36]. Dendrimer targets activated macrophages in the injured cornea upon subconjunctival administration, suggesting enhanced delivery and availability of corticosteroids (e.g., dexamethasone) to the very cells responsible for corneal inflammation [22]. ...
Purpose:
To investigate the efficacy of a single subconjunctival injection of dendrimer-dexamethasone to treat dry eye in a rabbit model of induced autoimmune dacryoadenitis (AID).
Method:
Dendrimer biodistribution after subconjuntival injection in AID animals was evaluated using Cy5-labelled dendrimer (D-Cy5) and confocal microscopy. Diseased animals were treated with free dexamethasone (Free-Dex), dendrimer-dexamethasone (D-Dex), or saline via a single subconjunctival injection. The efficacy was evaluated using various clinical evaluations, such as Schirmer's test, tear breakup time (TBUT), and fluorescein and rose bengal staining. Histopathology was evaluated by H&E staining and immunostaining. Levels of inflammatory cytokines and aquaporin proteins in the LGs were determined by real-time PCR.
Result:
Subconjunctivally administered dendrimers selectively localized in the inflamed LGs, and were taken up by the infiltrated cells. At two weeks post-treatment, the D-Dex group showed improved clinical evaluations. No significant changes were observed in other groups. H&E staining demonstrated, less inflammatory cell infiltration and fewer atrophic acini in D-Dex group, compared to those treated with saline or Free-Dex. Immunohistochemistry demonstrated that the intensity of CD-18 (+) and RTLA (+) was weaker in LGs in the D-Dex group than in other treatment rabbits. Pro-inflammatory gene expression levels of MMP9, IL6, IL8, and TNFα were significantly decreased in the D-Dex group compared to the saline group.
Conclusion:
The dendrimer exhibits pathology-dependent biodistribution in the inflamed LGs. Subconjunctivally administered D-Dex suppressed LG inflammation, leading to partial recovery of LG function with clinical improvement in induced AID. Sjögren's patients may benefit from this targeted nanomedicine approach.
... 2,5 Intravitreal implants are currently being developed; these release the drug at a steady rate and could be an alternative in patients who are poorly controlled or are intolerant of repeated injections, systemic steroids or immunosuppressive agents. 32,33 It has been shown that they are not toxic and they maintain constant intraocular levels of the drug for a long period of time (3-6 months, peaking within the first week). 34 For instance, intraocular implants help reduce uveitic recurrences, reduce the need for adjuvant therapy and improve VA through the reduction of retinal thickness, as has been demonstrated by OCT studies. ...
The purpose of this paper is to conduct a review of studies on cystoid macular edema published in the last seven years. Cystoid macu-lar edema is a major cause of loss of visual acuity. It is the final common pathway of many diseases and can be caused by numerous processes including inflammatory, vascular, adverse drug reactions, retinal dystrophy or intraocular tumors. These processes disrupt the blood-retinal barrier, with fluid extravasation to the macular parenchyma. Imaging tests are essential for both detection and monitoring of this pathology. Fluorescein angiography and autofluorescence show the leakage of liquid from perifoveal vessels into the tissue where it forms cystic spaces. Optical coherence tomography is currently the gold standard technique for diagnosis and monitoring. This allows objective measurement of retinal thickness, which correlates with visual acuity and provides more complete morphological information. Based on the underlying etiology, the therapeutic approach can be either surgical or medical with anti-inflammatory drugs. We found that disruption of the blood-retinal barrier for various reasons is the key point in the pathogenesis of cystoid macular edema, therefore we believe that studies on its treatment should proceed on this path.
Purpose:
To evaluate time to first additional treatment following intravitreal 0.19 mg fluocinolone acetonide (FAc) in non-infectious uveitis with posterior segment involvement (NIU-PS) in a real-world setting.
Methods:
Prospective observational study on 37 eyes (30 patients) with chronic or recurrent NIU-PS, treated with FAc after achieving control - indicated by absence of vitreous haze or clearly visible posterior pole. Over a median follow-up of 48.0 ± 0.0 months, we assessed time to and number of additional treatments, inflammatory activity, central subfield macular thickness (CSMT), visual acuity (VA) and intraocular pressure (IOP).
Results:
Restricted mean time to first adjuvant treatment was 31.9 ± 2.97 months, with 52.8% requiring no additional treatment ≥ 48 months. VA remained stable (baseline 0.56 ± 0.44 logMAR, p = 0.86). A negative correlation was found between the number of prior steroid implants (DEX-I) and time to additional treatment (r = -0.44, p = 0.001). For up to 24 months, FAc reduced anterior chamber flare (0.44 ± 0.81 to 0.00 ± 0.00, p < 0.001), vitreous haze (0.28 ± 0.51 to 0.00 ± 0.00, p = 0.01), and CSMT (407.1 ± 135.9 µm at baseline to 324.2 ± 75.7 µm at M24, p = 0.001). Within 48 months, ocular hypertension (≥25 mmHg) occurred in 22.2% of eyes (8/36), with 19.4% (7/36) requiring new-onset IOP-lowering drops.
Conclusion:
FAc demonstrated efficacy in managing low-grade NIU-PS, reducing the need for additional treatments and controlling intraocular inflammation for an average of 32 months.
The challenge of poor medication adherence in the management of chronic diseases remains a pivotal issue, contributing significantly to the disparity between real-world effectiveness and clinical trial outcomes. Conventional strategies aimed at improving adherence through patient education and empowerment have often proven intricate and largely inefficacious. In contrast, long-acting (LA) medicines represent a transformative approach to overcoming the adherence barrier. LA formulations offer simplified dosing regimens, reduced treatment burdens, heightened patient acceptability, and broader public health benefits. This chapter focuses on currently approved LA medicines and their global utilization in the management of chronic conditions such as psychosis, contraception, chronic ocular diseases, and HIV-1 infection. Notably, LA medicines have demonstrated a positive impact on patient acceptability and adherence rates across diverse disease categories. Furthermore, this chapter sheds light on the underexplored potential of LA medicines in addressing other chronic ailments such as osteoporosis, viral hepatitis, and various chronic viral infections, as well as cardiovascular diseases and diabetes. Emphasizing the importance of cost-effective, self-administrable, discreet, and reversible LA medicines with improved pharmacokinetics featuring a shorter PK tail, we highlight the potential for these innovations to significantly enhance the global adoption and application of LA medicines.
Background/Objectives: This review examines the evolution of lyotropic liquid crystals (LLCs) in ocular drug delivery, focusing on their ability to address the challenges associated with traditional ophthalmic formulations. This study aims to underscore the enhanced bioavailability, prolonged retention, and controlled release properties of LLCs that significantly improve therapeutic outcomes. Methods: This review synthesizes data from various studies on both bulk-forming LLCs and liquid crystal nanoparticles (LCNPs). It also considers advanced analytical techniques, including the use of machine learning and AI-driven predictive modeling, to forecast the phase behavior and molecular structuring of LLC systems. Emerging technologies in biosensing and real-time diagnostics are discussed to illustrate the broader applicability of LLCs in ocular health. Results: LLCs are identified as pivotal in promoting targeted drug delivery across different regions of the eye, with specific emphasis on the tailored optimization of LCNPs. This review highlights principal categories of LLCs used in ocular applications, each facilitating unique interactions with physiological systems to enhance drug efficacy and safety. Additionally, novel applications in biosensing demonstrate LLCs’ capacity to improve diagnostic processes. Conclusions: Lyotropic liquid crystals offer transformative potential in ocular drug delivery by overcoming significant limitations of conventional delivery methods. The integration of predictive technologies and biosensing applications further enriches the utility of LLCs, indicating a promising future for their use in clinical settings. This review points to continued advancements and encourages further research in LLC technology to maximize its therapeutic benefits.
Background/Objectives: This review examines the evolution of lyotropic liquid crystals (LLCs) in ocular drug delivery, focusing on their ability to address the challenges associated with traditional ophthalmic formulations. The study aims to underscore the enhanced bioavailability, prolonged retention, and controlled release properties of LLCs that significantly improve therapeutic outcomes; Methods: The review synthesizes data from various studies on both bulk-forming LLCs and liquid crystal nanoparticles (LCNPs). It also considers advanced analytical techniques, including the use of machine learning and AI-driven predictive modeling, to forecast the phase behavior and molecular structuring of LLC systems. Emerging technologies in biosensing and real-time diagnostics are discussed to illustrate the broader applicability of LLCs in ocular health; Results: LLCs are identified as pivotal in promoting targeted drug delivery across different regions of the eye, with specific emphasis on the tailored optimization of LCNPs. The review highlights principal categories of LLCs used in ocular applications, each facilitating unique interactions with physiological systems to enhance drug efficacy and safety. Additionally, novel applications in biosensing demonstrate LLCs' capacity to improve diagnostic processes; Conclusions: Lyotropic liquid crystals offer transformative potential in ocular drug delivery by overcoming significant limitations of conventional delivery methods. The integration of predictive technologies and biosensing applications further enriches the utility of LLCs, indicating a promising future for their use in clinical settings. This review points to continued advancements and encourages further research in LLC technology to maximize its therapeutic benefits.
Treatment of ocular diseases presents unique challenges and opportunities for the clinician and for the clinical pharmacologist. Ophthalmic pharmaceuticals, typically given as liquids, require consideration of solubility, physiological pH, and osmolarity, as well as sterility and stability, which in turn requires optimal pharmaceutics. Ocular tissue levels are challenging to obtain in humans, and the clinical pharmacokinetics is typically blood levels, which are primarily related to safety, rather than efficacy. The eye is a closed compartment with multiple physiological barriers with esterases and transporters, but relatively little cytochrome oxidases. Delivery routes include topical, intravitreal, and systemic. Patient dosing involves not only adherence issues common to all chronic diseases, but also performance requirements on eye drop instillation. Therapeutically, ocular diseases and their pharmacological treatments include both those analogous to systemic diseases (e.g., inflammation, infection, and neuronal degeneration) and those unique to the eye (e.g., cataract and myopia).
Eye drops represent the traditional form of medication delivery for the eyes, constituting approximately 90% of the presently available ophthalmic formulations. While they are generally well-received by patients, a significant challenge associated with eye drops is the rapid loss of medication before it reaches the cornea. The creation of new systems and means of drug delivery is important for solving the main problems of medicine – improving the therapeutic efficiency, tolerability, and safety of medical therapy. In the treatment of numerous of eye diseases, the main problem is creating a constant and sufficient concentration of drugs in the lesion due to the peculiarities of the anatomical and physiological structure of the eyeball. New approaches to non-invasive drug delivery are being developed, such as eye implants, contact lenses, as well as drug delivery systems based on nanoparticles, micelles, dendrimers, microneedles and liposomes. In situ gelation systems are also the subject of study and promising developments. Combining drugs within conventional delivery systems has the potential to pave the way for enhanced outcomes and improved therapeutic responses, particularly for systems that have previously shown limited effectiveness. This review discusses current understanding and recent discoveries attributed the utilisation of drug delivery systems in ophthalmology, including the characteristics, advantages, and disadvantages of each class of delivery system.
Background:
Uveitis is a term used to describe a group of intraocular inflammatory diseases. Uveitis is the fifth most common cause of vision loss in high-income countries, with the highest incidence of disease in the working-age population. Corticosteroids are the mainstay of treatment for all subtypes of non-infectious uveitis. They can be administered orally, topically with drops, by periocular (around the eye) or intravitreal (inside the eye) injection, or by surgical implantation.
Objectives:
To determine the efficacy and safety of steroid implants in people with chronic non-infectious posterior uveitis, intermediate uveitis, and panuveitis.
Search methods:
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register), MEDLINE Ovid, Embase, PubMed, LILACS, and three trials registries to November 2021.
Selection criteria:
We included randomized controlled trials comparing either fluocinolone acetonide (FA) or dexamethasone (DEX) intravitreal implants with standard-of-care therapy or sham procedures, with at least six months of follow-up after treatment. We included studies that enrolled participants of all ages, who had chronic non-infectious posterior uveitis, intermediate uveitis, or panuveitis with vision that was better than hand-motion.
Data collection and analysis:
We applied standard Cochrane methodology.
Main results:
We included data from four trials (683 participants, 907 eyes) that compared corticosteroid implants with either sham or standard-of-care therapy. Study characteristics and risk of bias Of the two trials that compared corticosteroid implants with sham procedure, one examined a 0.18 mg FA implant, and the other, a 0.7 mg DEX implant. The other two trials compared a 0.59 mg FA implant with standard-of-care therapy, which included systemic corticosteroids and immunosuppressive medications, if needed. Considering improvement in visual acuity, we assessed the four trials to be at either low risk, or with some concerns of risk of bias across all domains. Findings Using sham procedure as control, combined results at the six-month primary time point suggested that corticosteroid implants may decrease the risk of uveitis recurrence by 60% (relative risk [RR] 0.40, 95% confidence interval [CI] 0.30 to 0.54; 2 trials, 282 participants; low-certainty evidence); and lead to a greater improvement in best-corrected visual acuity (BCVA; mean difference [MD] 0.15 logMAR, 95% CI 0.06 to 0.24; 1 trial, 153 participants; low-certainty evidence). Evidence based on a single-study report (146 participants) suggested that steroid implants may have no effects on visual functioning quality of life, measured on the National Eye Institute 25-Item Visual Function Questionnaire (MD 2.85, 95%CI -3.64 to 9.34; 1 trial, 146 participants; moderate-certainty evidence). Using standard-of care therapy as control, combined estimates at the 24-month primary time point suggested that corticosteroid implants were likely to decrease the risk of recurrence of uveitis by 54% (RR 0.46, 95% CI 0.35 to 0.60; 2 trials, 619 eyes). Combined estimates at 24 months also suggested that steroid implants may have little to no effects on improving BCVA (MD 0.05 logMAR, 95% CI -0.02 to 0.12; 2 trials, 619 eyes; low-certainty evidence). Evidence based on a single-study report (232 participants) suggested that steroid implants may have minimal clinical effects on visual functioning (MD 4.64, 95% CI 0.13 to 9.15; 1 trial, 232 participants; moderate-certainty evidence); physical functioning (SF-36 physical subscale MD 2.95, 95% CI 0.55 to 5.35; 1 trial, 232 participants; moderate-certainty evidence); or mental health (SF-36 mental subscale MD 3.65, 95% CI 0.52 to 6.78; 1 trial, 232 participants; moderate-certainty evidence); but not on EuroQoL (MD 6.17, 95% CI 1.87 to 10.47; 1 trial, 232 participants; moderate-certainty evidence); or EuroQoL-5D scale (MD 0.02, 95% CI -0.04 to 0.08; 1 trial, 232 participants; moderate-certainty evidence). Adverse effects Compared with sham procedures, corticosteroid implants may slightly increase the risk of cataract formation (RR 2.69, 95% CI 1.17 to 6.18; 1 trial, 90 eyes; low-certainty evidence), but not the risk of cataract progression (RR 2.00, 95% CI 0.65 to 6.12; 1 trial, 117 eyes; low-certainty evidence); or the need for surgery (RR 2.98, 95% CI 0.82 to 10.81; 1 trial, 180 eyes; low-certainty evidence), during up to 12 months of follow-up. These implants may increase the risk of elevated intraocular pressure ([IOP] RR 2.81, 95% CI 1.42 to 5.56; 2 trials, 282 participants; moderate-certainty evidence); and the need for IOP-lowering eyedrops (RR 1.85, 95% CI 1.05 to 3.25; 2 trials, 282 participants; moderate-certainty evidence); but not the need for IOP-lowering surgery (RR 0.72, 95% CI 0.13 to 4.17; 2 trials, 282 participants; moderate-certainty evidence). Evidence comparing the 0.59 mg FA implant with standard-of-care suggested that the implant may increase the risk of cataract progression (RR 2.71, 95% CI 2.06 to 3.56; 2 trials, 210 eyes; low-certainty evidence); and the need for surgery (RR 2.98, 95% CI 2.33 to 3.79; 2 trials, 371 eyes; low-certainty evidence); along with the risk of elevated IOP (RR 3.64, 95% CI 2.71 to 4.87; 2 trials, 605 eyes; moderate-certainty evidence); and the need for medical (RR 3.04, 95% CI 2.36 to 3.91; 2 trials, 544 eyes; moderate-certainty evidence); or surgical interventions (RR 5.43, 95% CI 3.12 to 9.45; 2 trials, 599 eyes; moderate-certainty evidence). In either comparison, these implants did not increase the risk for endophthalmitis, retinal tear, or retinal detachment (moderate-certainty evidence).
Authors' conclusions:
Our confidence is limited that local corticosteroid implants are superior to sham therapy or standard-of-care therapy in reducing the risk of uveitis recurrence. We demonstrated different effectiveness on BCVA relative to comparators in people with non-infectious uveitis. Nevertheless, the evidence suggests that these implants may increase the risk of cataract progression and IOP elevation, which will require interventions over time. To better understand the efficacy and safety profiles of corticosteroid implants, we need future trials that examine implants of different doses, used for different durations. The trials should measure core standard outcomes that are universally defined, and measured at comparable follow-up time points.
To investigate the efficacy and safety of dexamethasone (DEX) implant, Ozurdex ®, as an adjunctive treatment for refractory Behçet's uveitis (BU), a total of 61 patients (80 eyes) were included in this cross-sectional study and divided into the non-DEX and DEX groups. After >12 months of treatment, the improvement in the fluorescein angiography score and vitritis score was significantly higher in the DEX group than in the non-DEX group. Although the posterior capsule opacification score was exacerbated, the rate of low-dose systemic glucocorticoid was higher and the relapse times were fewer in the DEX group. Therefore, Ozurdex® is an effective and safe option for patients with BU that are refractory to systemic immunosuppressant treatments by controlling vasculitis, stabilizing vitreous inflammation, preventing recurrence, and reducing daily glucocorticoid doses.
Background:
Uveitis is a term used to describe a group of intraocular inflammatory diseases. Uveitis is the fifth most common cause of vision loss in high-income countries, with the highest incidence of disease in the working-age population. Corticosteroids are the mainstay of treatment for all subtypes of non-infectious uveitis. They can be administered orally, topically with drops, by periocular (around the eye) or intravitreal (inside the eye) injection, or by surgical implantation.
Objectives:
To determine the efficacy and safety of steroid implants in people with chronic non-infectious posterior uveitis, intermediate uveitis, and panuveitis.
Search methods:
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register), MEDLINE Ovid, Embase, PubMed, LILACS, and three trials registries to November 2021. SELECTION CRITERIA: We included randomized controlled trials comparing either fluocinolone acetonide (FA) or dexamethasone (DEX) intravitreal implants with standard-of-care therapy or sham procedures, with at least six months of follow-up after treatment. We included studies that enrolled participants of all ages, who had chronic non-infectious posterior uveitis, intermediate uveitis, or panuveitis with vision that was better than hand-motion.
Data collection and analysis:
We applied standard Cochrane methodology.
Main results:
We included data from four trials (683 participants, 907 eyes) that compared corticosteroid implants with either sham or standard-of-care therapy. Study characteristics and risk of bias Of the two trials that compared corticosteroid implants with sham procedure, one examined a 0.18 mg FA implant, and the other, a 0.7 mg DEX implant. The other two trials compared a 0.59 mg FA implant with standard-of-care therapy, which included systemic corticosteroids and immunosuppressive medications, if needed. We assessed the four trials to be at either low risk, or with some concerns of risk of bias across all domains. Findings Using sham procedure as control, combined results at the six-month primary time point suggested that corticosteroid implants may decrease the risk of uveitis recurrence by 60% (relative risk [RR] 0.40, 95% confidence interval [CI] 0.30 to 0.54; 2 trials, 282 participants; low-certainty evidence); and lead to a greater improvement in best-corrected visual acuity (BCVA; mean difference [MD] 0.22 logMAR, 95% CI 0.13 to 0.31; 1 trial, 153 participants; low-certainty evidence). Evidence based on a single-study report (146 participants) suggested that steroid implants may have no effects on visual functioning quality of life, measured on the National Eye Institute 25-Item Visual Function Questionnaire (MD 2.85, 95%CI -3.64 to 9.34; 1 trial, 146 participants; moderate-certainty evidence). Using standard-of care therapy as control, combined estimates at the 24-month primary time point suggested that corticosteroid implants were likely to decrease the risk of recurrence of uveitis by 54% (RR 0.46, 95% CI 0.35 to 0.60; 2 trials, 619 eyes). Combined estimates at 24 months also suggested that steroid implants may have little to no effects on BCVA (MD 0.05 logMAR, 95% CI -0.02 to 0.12; 2 trials, 619 eyes; low-certainty evidence). Evidence based on a single-study report (232 participants) suggested that steroid implants may have minimal clinical effects on visual functioning (MD 4.64, 95% CI 0.13 to 9.15; 1 trial, 232 participants; moderate-certainty evidence); physical functioning (SF-36 physical subscale MD 2.95, 95% CI 0.55 to 5.35; 1 trial, 232 participants; moderate-certainty evidence); or mental health (SF-36 mental subscale MD 3.65, 95% CI 0.52 to 6.78; 1 trial, 232 participants; moderate-certainty evidence); but not on EuroQoL (MD 6.17, 95% CI 1.87 to 10.47; 1 trial, 232 participants; moderate-certainty evidence); or EuroQoL-5D scale (MD 0.02, 95% CI -0.04 to 0.08; 1 trial, 232 participants; moderate-certainty evidence). Adverse effects Compared with sham procedures, corticosteroid implants may slightly increase the risk of cataract formation (RR 2.69, 95% CI 1.17 to 6.18; 1 trial, 90 eyes; low-certainty evidence), but not the risk of cataract progression (RR 2.00, 95% CI 0.65 to 6.12; 1 trial, 117 eyes; low-certainty evidence); or the need for surgery (RR 2.98, 95% CI 0.82 to 10.81; 1 trial, 180 eyes; low-certainty evidence), during up to 12 months of follow-up. These implants may increase the risk of elevated intraocular pressure ([IOP] RR 2.81, 95% CI 1.42 to 5.56; 2 trials, 282 participants; moderate-certainty evidence); and the need for IOP-lowering eyedrops (RR 1.85, 95% CI 1.05 to 3.25; 2 trials, 282 participants; moderate-certainty evidence); but not the need for IOP-lowering surgery (RR 0.72, 95% CI 0.13 to 4.17; 2 trials, 282 participants; moderate-certainty evidence). Evidence comparing the 0.59 mg FA implant with standard-of-care suggested that the implant may increase the risk of cataract progression (RR 2.71, 95% CI 2.06 to 3.56; 2 trials, 210 eyes; low-certainty evidence); and the need for surgery (RR 2.98, 95% CI 2.33 to 3.79; 2 trials, 371 eyes; low-certainty evidence); along with the risk of elevated IOP (RR 3.64, 95% CI 2.71 to 4.87; 2 trials, 605 eyes; moderate-certainty evidence); and the need for medical (RR 3.04, 95% CI 2.36 to 3.91; 2 trials, 544 eyes; moderate-certainty evidence); or surgical interventions (RR 5.43, 95% CI 3.12 to 9.45; 2 trials, 599 eyes; moderate-certainty evidence). In either comparison, these implants did not increase the risk for endophthalmitis, retinal tear, or retinal detachment (moderate-certainty evidence). AUTHORS' CONCLUSIONS: Our confidence is limited that local corticosteroid implants are superior to sham therapy or standard-of-care therapy in reducing the risk of uveitis recurrence. We demonstrated different effectiveness on BCVA relative to comparators in people with non-infectious uveitis. Nevertheless, the evidence suggests that these implants may increase the risk of cataract progression and IOP elevation, which will require interventions over time. To better understand the efficacy and safety profiles of corticosteroid implants, we need future trials that examine implants of different doses, used for different durations. The trials should measure core standard outcomes that are universally defined, and measured at comparable follow-up time points.
Introduction:
Ocular long-acting injectables and implants (LAIIs) deliver drug at a controlled release rate over weeks to years. A reduced dose frequency eases the treatment burden on patients, minimizes the potential for treatment-related adverse effects, and improves treatment adherence and persistence.
Areas covered:
This review provides a comprehensive landscape of ocular LAII drug delivery technologies with clinical precedent, including eight commercial products and 27 clinical programs. Analysis of this landscape, and the specific technologies with the greatest precedent, provides instructive lessons for researchers interested in this space and insights into the direction of the field.
Expert opinion:
Further technological advancement is required to create biodegradable LAIIs with extended release durations and LAIIs that are compatible with a broader array of therapeutic modalities. In the future, ocular LAII innovations can be applied to diseases with limited treatment options, prophylactic treatment at earlier stages of disease, and cost-effective treatment of ocular diseases in global health settings.
The uveitides are a heterogeneous group of diseases characterized by inflammation inside the eye. The uveitides are classified as infectious or non-infectious. The non-infectious uveitides, which are presumed to be immune mediated, can be further divided into those that are associated with a known systemic disease and those that are eye limited,—ie, not associated with a systemic disease. The ophthalmologist identifies the specific uveitic entity by medical history, clinical examination, and ocular imaging, as well as supplemental laboratory testing, if indicated. Treatment of the infectious uveitides is tailored to the particular infectious organism and may include regional and/or systemic medication. First line treatment for non-infectious uveitides is corticosteroids that can be administered topically, as regional injections or surgical implants, or systemically. Systemic immunosuppressive therapy is used in patients with severe disease who cannot tolerate corticosteroids, require chronic corticosteroids at >7.5 mg/day prednisone, or in whom the disease is known to respond better to immunosuppression. Management of many of these diseases is optimized by coordination between the ophthalmologist and rheumatologist or internist.
Uveitic macular edema is a significant cause of visual impairment in most uveitis types. Treatment options of uveitis have advanced remarkably in recent years. Up to now, corticosteroids remain the mainstay of treatment. Nonsteroidal immunomodulators, and recently the biologic agents, which can reinforce efficacy and enable discontinuation or reduction of steroids to maintenance doses, are becoming increasingly popular in the management of uveitic macular edema. Several medications can be used in intraocular delivery and more and more sustained releasing implants are being developed. This review will briefly focus on the review of local therapy for the management of cystoid macular edema in uveitis, as many of these novel approaches are currently being evaluated in clinical trials.
Introduction: Drug eluting implants offer patient convenience and improved compliance through less frequent dosing, eliminating repeated, painful injections and providing localized, site specific delivery with applications in contraception, ophthalmology, and oncology.
Areas covered: This review provides an overview of available implant products, design approaches, biodegradable and non-biodegradable polymeric materials, and fabrication techniques with a focus on commercial applications and industrial drug product development. Developing trends in the field, including expanded availability of suitable excipients, development of novel materials, scaled down manufacturing process, and a wider understanding of the implant development process are discussed and point to opportunities for differentiated drug eluting implant products.
Expert opinion: In the future, long-acting implants will be important clinical tools for prophylaxis and treatment of global health challenges, especially for infectious diseases, to reduce the cost and difficulty of treating chronic indications, and to prolong local delivery in difficult to administer parts of the body. These products will help improve patient safety, adherence, and comfort.
Introduction:
To describe the ocular inflammatory and iatrogenic complications in a cohort of uveitic patients treated in an Italian referral centre.
Material and methods:
Retrospective non-comparative case series. Medical history and clinical findings of all consecutive patients referred to the uveitis center of Pisa University from January 2015 to January 2017 were reviewed. Only patients with at least three follow-up visits in our center were included in our series.
Results:
Three hundred and eighty-nine patients were visited in our center during study period; only 142 patients (90 men and 52 female) satisfied the inclusion criteria. Mean age at presentation was 41 ± 14 years. The most common ocular feature was anterior uveitis (46%) and was mainly unilateral. A specific etiological diagnosis was established in 61% of patients. At presentation, 71.43% of patients were on medical therapy for rheumatic disease; 42.86% of patients used systemic steroids Cataract and ocular hypertension were the most common ocular complications during the study period but were not statistically related to systemic steroid treatment.
Conclusions:
Systemic steroids treatment in uveitis patients does not seem to increase the risk of iatrogenic complications such as cataract and glaucoma. In our series, increasing age appears to be the main risk factor for cataract and glaucoma development. Key points • Cataract, ocular hypertension, and glaucoma are the most common iatrogenic complications. • Systemic steroids can be safely used in uveitis patients.
Purpose: To determine factors conferring an increased risk of developing ocular hypertension secondary to the fluocinolone acetonide (FA) sustained-release surgical implant (Retisert).
Design: Retrospective, observational case series.
Methods: Patients with a history of chronic noninfectious posterior uveitis undergoing naïve surgical FA implantation from 2007 to 2018 at the University of Colorado were studied. Patient demographics and multiple clinical measures were noted one year before and after FA implantation.
Results: Twenty-nine eyes of 21 patients were studied. The median age experiencing an IOP rise vs median age experiencing no IOP rise post-FA implantation was 27.0 and 54.0 years old, respectively (p = .01). A pre-FA implant risk factor of needing future glaucoma surgery after FA implantation is prior to maximum IOP (p = .02).
Conclusions: A risk factor of elevated post-FA implantation IOP includes younger age. A potential risk factor for glaucoma surgery after FA implantation was higher maximum IOP before FA implantation.
Local application of exogenous agents with neurotrophic properties enhances the regenerative capacity of injured neurons, especially following reconstructions of long nerve gaps and delayed nerve repairs. Recent advances in biomaterials and biomedical engineering have provided options for the sustained and controlled release of macromolecules to the peripheral nerve. Here, we review five methods for delivering macromolecules to the peripheral nerve including mini-osmotic pumps, hydrogel-based delivery systems, nerve guidance conduits, electrospun fibers, and nerve wraps. In addition to controlling the release of bioactive macromolecules, the ease of clinical use and versatility in implantation at a variety of "real-world" anatomical locations are key factors in designing an ideal delivery system. The incorporation of both mechanical and biological cues into such devices also helps optimize these systems.
Purpose
To present the evolution of intravitreal therapy for retinal diseases and its impact on clinical practice.
Design
Retrospective literature review and personal perspective.
Methods
Retrospective literature review and personal perspective.
Results
Pharmacotherapeutic advances in retinal disease have been remarkable over the last 25 years. Almost all of the new drugs developed have required intravitreal administration to be highly effective, leading to an exponential increase in the annual number of intravitreal injections given. The use of intravitreal antibiotic injections to treat endophthalmitis, usually on a one-time basis, first familiarized ophthalmologists with this method of drug delivery. Ganciclovir was the first widely available, relatively inexpensive, compounded drug that was used for repeat intravitreal injection to treat a chronic retinal disease, followed by triamcinolone for diabetic macular edema and bevacizumab for neovascular AMD. Ganciclovir was formulated for sustained-release drug delivery to avoid frequent intravitreal injections, a goal that has been more elusive for anti-VEGF drugs. Political obstacles encountered while conducting some of the trials to evaluate these treatments were substantial. Addressing the issues they raised led to important national policy changes that will impact the conduct of future clinical trials. The first comparative efficacy trial of intravitreal therapies was the Comparison of AMD Treatments Trials (CATT). The primary results from CATT and the many publications that followed continue to shape the use of intravitreal therapy today.
Conclusion
Intravitreal therapy has proven highly effective for the treatment of many retinal diseases. The treatment burden for patients from numerous injections, the cost to health care systems, and the impact on workflows in clinical practice have been substantial. Efforts to develop effective intravitreal therapies with reduced treatment burden and cost are ongoing.
Purpose:
To evaluate the safety and tolerability of conjunctival rings (CRs), a novel device for drug delivery to the posterior segment of the eye.
Methods:
In animal studies, CRs containing 5% dexamethasone sodium phosphate (DSP) or vehicle solution were placed on the right and left eyes of C57BL/6J mice, respectively. Contact lenses (CLs) containing vehicle solution were used as a control. Twenty-four hours after placement of the CRs, corneal fluorescein staining was graded based on the McDonald-Shadduck scoring system, ranging from 0 to 4. In humans, CRs containing vehicle solution were placed on the right eye of healthy volunteers for 9 hours. The corneal curvature, corneal thickness, intraocular pressure, visual acuity, tear production (Schirmer I test), tear film break-up time and fluorescein staining scores of the cornea (scores ranging from 0 to 3) and conjunctiva (scores ranging from 0 to 6) were assessed before and after wearing the CRs. The release characteristics of DSP from CRs were also evaluated.
Results:
In animal experiments, corneal fluorescein staining scores were 1 or less in all the groups, and there was no significant difference between the CR group and the CL group. In the preclinical safety evaluation of CR for humans, ophthalmic examination revealed that CR caused no significant changes in all the parameters investigated including corneal curvature (p = 0.77), corneal thickness (p = 0.96), intraocular pressure (p = 0.59), visual acuity (p = 0.14), Schirmer I test results (p = 0.76), tear film break-up time (p = 0.68), corneal fluorescein staining scores (p = 0.64), and conjunctival fluorescein staining scores (p = 0.52). The DSP release from CRs occurs within a few hours, which is similar to the drug-release property of medicated CL, as reported previously.
Conclusions:
The current data showed the safety and tolerability of CR as a drug delivery device for the treatment of posterior segment diseases.
The fluocinolone acetonide (Retisert™) 0.59-mg implant is a device approved by the Food and Drug Administration for the management of non-infectious posterior uveitis. Its intraocular sustained-release design allows it to circumvent the side effects of traditional systemic corticosteroid treatment and avoid the drawbacks of frequent and repeated local drug administration. This chapter will review the current literature regarding efficacy and safety of the implant.
Macular edema is the leading cause of vision loss in patients with uveitis. Chronic edema can lead to permanent retinal damage and atrophy; therefore, treatment should be initiated early and continue until complete resolution. Corticosteroids have been the mainstay of therapy and can be given topically, as a periocular or intravitreal injection, via an implantable depot preparation, or orally. Risks of cataract and glaucoma can limit the ongoing use of steroids, and other agents may be indicated. Alternative treatments including intravitreal anti-VEGF agents, intravitreal methotrexate, subcutaneous interferon alpha, and systemic antitumor necrosis factor agents have also demonstrated efficacy in treating inflammatory macular edema. The decision about which agent is most appropriate can be challenging and should be tailored to the clinical scenario.
This is the protocol for a review and there is no abstract. The objectives are as follows: To determine the efficacy and safety of steroid implants in patients with chronic non-infectious posterior uveitis, intermediate uveitis and panuveitis.
Background:
Uveitis is a term used to describe a heterogeneous group of intraocular inflammatory diseases of the anterior, intermediate, and posterior uveal tract (iris, ciliary body, choroid). Uveitis is the fifth most common cause of vision loss in high-income countries, accounting for 5% to 20% of legal blindness, with the highest incidence of disease in the working-age population.Corticosteroids are the mainstay of acute treatment for all anatomical subtypes of non-infectious uveitis and can be administered orally, topically with drops or ointments, by periocular (around the eye) or intravitreal (inside the eye) injection, or by surgical implantation.
Objectives:
To determine the efficacy and safety of steroid implants in people with chronic non-infectious posterior uveitis, intermediate uveitis, and panuveitis.
Search methods:
We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (Issue 10, 2015), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2015), EMBASE (January 1980 to November 2015), PubMed (1948 to November 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to November 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 15 April 2013), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic search for studies. We last searched the electronic databases on 6 November 2015.We also searched reference lists of included study reports, citation databases, and abstracts and clinical study presentations from professional meetings.
Selection criteria:
We included randomized controlled trials comparing either fluocinolone acetonide (FA) or dexamethasone intravitreal implants with standard-of-care therapy with at least six months of follow-up after treatment. We included studies that enrolled participants of all ages who had chronic non-infectious posterior uveitis, intermediate uveitis, or panuveitis with vision that was better than hand-motion.
Data collection and analysis:
Two review authors independently reviewed studies for inclusion. Two review authors independently extracted data and assessed the risk of bias for each study.
Main results:
We included data from two studies (619 eyes of 401 participants) that compared FA implants with standard-of-care therapy. Both studies used similar standard-of-care therapy that included administration of prednisolone and, if needed, immunosuppressive agents. The studies included participants from Australia, France, Germany, Israel, Italy, Portugal, Saudi Arabia, Spain, Switzerland, Turkey, the United Kingdom, and the United States. We assessed both studies at high risk of performance and detection bias.Only one study reported our primary outcome, recurrence of uveitis at any point during the study through 24 months. The evidence, judged as moderate-quality, showed that a FA implant probably prevents recurrence of uveitis compared with standard-of-care therapy (risk ratio (RR) 0.29, 95% confidence interval (CI) 0.14 to 0.59; 132 eyes). Both studies reported safety outcomes, and moderate-quality evidence showed increased risks of needing cataract surgery (RR 2.98, 95% CI 2.33 to 3.79; 371 eyes) and surgery to lower intraocular pressure (RR 7.48, 95% CI 3.94 to 14.19; 599 eyes) in the implant group compared with standard-of-care therapy through two years of follow-up. No studies compared dexamethasone implants with standard-of-care therapy.
Authors' conclusions:
After considering both benefits and harms reported from two studies in which corticosteroids implants were compared with standard-of-care therapy, we are unable to conclude that the implants are superior to traditional systemic therapy for the treatment of non-infectious uveitis. These studies exhibited heterogeneity in design and outcomes that measured efficacy. Pooled findings regarding safety outcomes suggest increased risks of post-implant surgery for cataract and high intraocular pressure compared with standard-of-care therapy.
Over the past 2 decades therapy for the treatment of intraocular inflammation (uveitis) has developed into a highly differentiated approach with an increasing number of drug options. This paper primarily summarises literature from the past 5 years (2000 to May 2004), gives an update on systemic immunosuppressive therapy for non-infectious uveitis and speculates about new developments that could become relevant in the near future for the treatment of uveitis patients. The spectrum of immunosuppressive drugs has been notably expanded by tumor necrosis factor inhibitors, but with some limitations to uveitis. Behcet's disease is an example of uveitis where a multisystem disorder can affect the eye very severely. This clinical example has been used to investigate the utility of many different types of immunosuppressive therapies and the clinical approach is extensively discussed in this review. An accompanying table summarises the proposed mode of action, standard dosage, common adverse effects, as well as estimated cost of current treatment options.
Sustained release of corticosteroids inside the eye has the inherent advantages of eliminating systemic side effects and providing long-term, continuous control of inflammation.
■ The fluocinolone acetonide intravitreal implant developed by Bausch & Lomb is approved by the US Food and Drug Administration and currently available in the USA. It demonstrates that local delivery can be effective in constantly controlling inflammation, reducing flare-ups, and maintaining vision.
■ Several other implantable devices are currently under study.
■ The anticipated side effects of cataract and glaucoma are produced by corticosteroid implants and must be carefully monitored.
■ The benefits of local control and no systemic side effects must be weighed against the associated local side effects in each patient.
Pars plana exudates in intermediate uveitis (IU) are associated with more severe vitreous disease and increased incidence of cystoid macular edema (CME).
■ Cryotherapy and laser photocoagulation are used in the treatment of the pars planitis variant of corticosteroid resistant IU.
■ Cryotherapy should be avoided in retinal detachment or marked peripheral vitreoretinal adhesions. A B-scan ultrasound may be needed.
■ Technique for cryotherapy:
- Peribulbar or sub-Tenon anesthesia.
- “Freeze-thaw-freeze” or “double row single freeze” of inferior snowbank.
- Treat contiguous, uninvolved retina (one third width of snowbank) and area with dense exudates.
- Average of 20 freezes per eye.
- Postoperative posterior sub-Tenon injection of long-acting corticosteroids and topical steroids.
■ Technique for laser photocoagulation:
- Topical anesthesia is preferred for office treatment.
- Endophotocoagulation may be performed during pars plana posterior vitrectomy, under peribulbar, retrobulbar or general anesthesia.
- Nonconfluent, grayish laser marks, 300–500-μm wide, 0.2 s duration.
The grading of diabetic retinopathy is based on the concept that a hierarchy of stages can be defined, where the higher the grade, the higher the risk of suffering visual loss. The grading scale reflects the natural course of the disease in its unrelenting and most devastating form. In reality, diabetic retinopathy can regress both spontaneously and after therapeutic intervention. To construct or validate a grading scale, rates of progression to visual loss or another endpoint that is meaningful to the patient must be measured. Grading scales constructed for scientific and regulatory purposes, such as the study of new interventions, are made with the purpose of achieving maximum sensitivity for change in retinopathy. Interventional trials may then result in selected grades being validated and found useful for guiding interventions such as photocoagulation for proliferative diabetic retinopathy or diabetic macular edema. The timely identification of patients who reach interventional thresholds is the purpose subserved by simpler grading scales used in clinical screening practice.
Uveitis often runs a chronic course requiring long-term therapy. Topical treatment results in poor intravitreal penetration, and systemic therapy is associated with significant side effects. The authors investigated whether an intravitreal sustained-release dexamethasone device was effective in the treatment of severe panuveitis in a rabbit model.
Twenty New Zealand white rabbits were immunized twice subcutaneously with 10 mg of Mycobacterium tuberculosis H37Ra antigen. Twelve days later, sustained-release dexamethasone devices were implanted into the vitreous of the right eye of 10 rabbits. Ten control rabbits received a sham device. One day later, rabbits were challenged with an intravitreal injection of 33 micrograms of antigen. Three animals in each group were sacrificed on post-challenge days 7 and 13 for aqueous white blood cell (WBC) count, protein determination, and histologic examination. To simulate chronic inflammation with exacerbations, the eight remaining eyes were rechallenged with intravitreal antigen on day 15 and were observed for 3 1/2 months. Inflammation was graded clinically by two masked observers. Retinal function was evaluated by electroretinography (ERG). Light microscopy was used to evaluate the eyes histopathologically. The amount of residual drug in the devices was measured on day 13 and at the end of the experiment.
By all clinical criteria measured--anterior chamber cells, flare, and vitreous opacity--treated eyes had significantly less inflammation than untreated eyes (P < 0.05). Clinical examination correlated well with objective data. Both protein concentration (P < 0.05) and aqueous WBCs (P < 0.02) were approximately 10-fold higher, and ERGs were significantly depressed (P < 0.05) in untreated eyes compared to treated eyes. Histopathologic examination showed marked inflammation and tissue disorganization in the untreated compared to the treated eyes. After antigen rechallenge, inflammation in experimental eyes was still less than in control eyes. Late complications such as corneal neovascularization, cataract, and hypotony were also less in the treated eyes than in the untreated eyes. At the end of the experiment (99 days after device implantation), approximately 30% of drug remained in the devices.
The intravitreal sustained-release dexamethasone device is highly effective in suppressing inflammation and preventing complications after two episodes of experimental uveitis in a rabbit model for at least 3 1/2 months. This device may be useful in the management of patients with severe chronic posterior uveitis who cannot tolerate systemic or periocular therapy.
Uveitis is the comprehensive reference you need for a balanced approach to basic science and clinical application. Robert B. Nussenblatt and Scott M. Whitcup provide a cohesive and integrated discussion of the topic, covering everything from the role of surgery to AIDS to anterior uveitis and more. This new edition even includes full color throughout, 400 photographs and illustrations, and searchable access to the text online at expertconsult.com. Comprehensive yet readable, this resource packs everything you need in patient evaluation and management to achieve optimal results.
Objectives:
To examine the clearance of cyclosporine after intravitreal injection and to assess the kinetics and toxic effects of an intravitreal device that provides sustained delivery of cyclosporine.
Methods:
Rabbits were divided into two groups to evaluate (1) the elimination kinetics after 1-μg and 10-μg intravitreal injections of cyclosporine and (2) the levels produced after implantation of a device that contained cyclosporine over 6 months. The toxic effects of the intravitreal device over 6 months were assessed in rabbits and cynomolgus monkeys.
Results:
After the 10-μg injection, the half-life was longer (10.8 hours vs 4.2 hours) and the distribution volume was smaller (1.7 mL vs 3.2 mL) than after the 1-μg injection. This difference can be attributed to saturable partitioning of the drug. The device resulted in a vitreous concentration of approximately 500 ng/mL throughout the study period. In the rabbit it resulted in reversible lens opacification and decreased b-wave amplitude. This toxic effect was not detected in the monkey.
Conclusions:
The device produces sustained intravitreal levels of cyclosporine. Although it was associated with reversible toxic effects in the rabbit, it was well tolerated in primates. Sustained-release implants are a promising new treatment for chronic uveitis.
Objective: This study aimed to investigate the incidence of cystoid macular edema and anterior uveitis associated with the use of latanoprost. Design: A retrospective review of patients treated with latanoprost in the authors' practice between September 1, 1996, and August 1, 1997, was performed. Participants: Ninety-four patients and 163 eyes were studied. Intervention: Patients presenting with signs and symptoms of ocular inflammation while receiving latanoprost were noted, and their response to the discontinuation of the drug was recorded. Main Outcome Measures: The presence and degree of anterior uveitis and cystoid macular edema were measured. Results: Six (6.4%) of 94 patients (8 [4.9%] of 163 eyes) had anterior uveitis develop, and 2 (2.1%) of 94 patients (2 [1.2%] of 163 eyes) had cystoid macular edema develop while being treated with latanoprost. Conclusion: Although latanoprost is an effective ocular-hypotensive agent, the authors' experience with the drug has shown a significant incidence of anterior uveitis and cystoid macular edema. To the authors' knowledge, this is the first study to report the incidence of both cystoid macular edema and anterior uveitis associated with latanoprost therapy. Treating physicians should be aware of these potential complicating side effects of latanoprost.
The authors reviewed the outcome of extracapsular cataract extraction (ECCE) in 44 eyes of 38 patients with uveitis. Thirty-two of the 44 eyes received a posterior chamber lens implant; 87% of these achieved a stable visual acuity of 20/40 or better. Sixty-seven percent (8 of the 12 eyes) not receiving an implant achieved this level. The authors' results and current literature suggest that absolute control, preoperatively and postoperatively, of all uveitis inflammation and careful selection of patients as lens implant candidates are crucial for successful cataract surgery in uveitis patients. Complete removal of lens cortex and placement of an all-PMMA posterior chamber lens within the capsular bag are also believed to be important.
An implantable sustained release device has been developed to treat chronic disorders of the eye. The device, consisting of a central core of drug encased in layers of permeable and impermeable polymers, can be implanted subconjunctivally or intravitreally. This technique was used to develop a ganciclovir device which, when implanted into the vitreous, maintains therapeutic vitreous levels of drug for 8 months. Initial studies in patients with cytomegalovirus (CMV) retinitis indicate that this treatment may offer better control of the disease and fewer side effects than existing therapies. Cyclosporine A devices were prepared for the treatment of uveitis. Early data suggests that these devices maintain therapeutic levels in the vitreous for approximately 3 years. Work on efficacy and toxicity is continuing. Although clinical applications of these devices are likely to be restricted to diseases requiring chronic drug therapy, they can be used to investigate optimal delivery rates. Subconjunctivally implanted devices releasing 5-FU for 12 days maintained filters in cynomolgus monkeys for 3 months. Similar devices maintained low intraocular pressure in 75% of high risk filter patients.
To examine the clearance of cyclosporine after intravitreal injection and to assess the kinetics and toxic effects of an intravitreal device that provides sustained delivery of cyclosporine.
Rabbits were divided into two groups to evaluate (1) the elimination kinetics after 1-microgram and 10-microgram intravitreal injections of cyclosporine and (2) the levels produced after implantation of a device that contained cyclosporine over 6 months. The toxic effects of the intravitreal device over 6 months were assessed in rabbits and cynomolgus monkeys.
After the 10-microgram injection, the half-life was longer (10.8 hours vs. 4.2 hours) and the distribution volume was smaller (1.7 mL vs 3.2 mL) than after the 1-microgram injection. This difference can be attributed to saturable partitioning of the drug. The device resulted in a vitreous concentration of approximately 500 ng/mL throughout the study period. In the rabbit it resulted in reversible lens opacification and decreased b-wave amplitude. This toxic effect was not detected in the monkey.
The device produces sustained intravitreal levels of cyclosporine. Although it was associated with reversible toxic effects in the rabbit, it was well tolerated in primates. Sustained-release implants are a promising new treatment for chronic uveitis.
Sustained intravitreal levels of dexamethasone may be useful in the treatment of proliferative vitreoretinopathy (PVR). The preparation and evaluation of an implantable system for intravitreal sustained release of dexamethasone is described. Pellets of dexamethasone were coated in biocompatible, nonerodible polymers and the release rate tested in vitro. Devices were then implanted in the rabbit vitreous and the in vivo release rate and corresponding steady state vitreous concentration determined. Toxicity was also evaluated by histopathology and electrographic examination. Devices released dexamethasone at approximately 1 ug/hr in vitro and 1.5 ug/hr in vivo. When implanted into the vitreous intravitreal concentrations of approximately 2.5 +/- 1.2 ug/hr were maintained for over 3 months. Devices were well tolerated with no evidence of inflammation or retinal abnormalities.
Uveitis often is a chronic disease requiring long-term medical therapy. Despite treatment, the disease may be difficult to control and may produce serious, vision-threatening ocular complications. In this study, the authors determined whether an intravitreal cyclosporine-sustained delivery device was effective in the treatment of ocular inflammation in a rabbit model of uveitis.
New Zealand White rabbits were immunized subcutaneously with Mycobacterium tuberculosis H37Ra antigen. Fourteen days later, sustained-release cyclosporine devices were implanted into the vitreous cavity of the right eye of experimental rabbits. Control animals received sham devices. Seven days after device implantation, rabbits were challenged with an intravitreal injection of tuberculin antigen. To simulate chronic inflammation with exacerbations, some animals were rechallenged with intravitreal antigen on day 21 after device implantation. Inflammation was assessed clinically by a masked observer who graded anterior chamber cells, flare, corneal neovascularization, iris congestion, and vitreous opacity daily until day 7 and on day 13 after the initial intravitreous challenge, and on days 1 and 2 after the rechallenge. Retinal function was evaluated by electroretinography. Animals were killed 3, 6, 8, and 14 days after the initial intravitreal challenge and on the second day after rechallenge for aqueous leukocyte count, protein measurement, and histologic examination. The number of aqueous and peripheral blood proliferating lymphocytes and the subset of CD4+ T cells were determined by flow cytometry. High-performance liquid chromatography was used to measure cyclosporine A levels in vitreous and peripheral blood. Light microscopy was used to evaluate the eyes histopathologically.
By clinical criteria, treated eyes had significantly less inflammation than untreated eyes. The number of aqueous cells and protein concentration determined quantitatively paralleled the clinical assessment of anterior chamber cells and flare. The electroretinography B-wave was depressed significantly in untreated eyes compared with that of treated eyes (P < 0.02). Histopathologic examination results showed marked inflammation and tissue disorganization in untreated eyes, whereas cyclosporine-treated eyes had preserved architecture and greatly reduced inflammatory cells. Intravitreal cyclosporine remained at therapeutic levels for at least 6 months after intravitreal device implantation, whereas blood levels were low to nondetectable.
The intravitreal cyclosporine A device effectively suppresses ocular inflammation in a rabbit model of uveitis. This device may be useful in the treatment of patients with severe chronic uveitis who are intolerant to currently available therapies.
This study aimed to investigate the incidence of cystoid macular edema and anterior uveitis associated with the use of latanoprost.
A retrospective review of patients treated with latanoprost in the authors' practice between September 1, 1996, and August 1, 1997, was performed.
Ninety-four patients and 163 eyes were studied.
Patients presenting with signs and symptoms of ocular inflammation while receiving latanoprost were noted, and their response to the discontinuation of the drug was recorded.
The presence and degree of anterior uveitis and cystoid macular edema were measured.
Six (6.4%) of 94 patients (8 [4.9%] of 163 eyes) had anterior uveitis develop, and 2 (2.1%) of 94 patients (2 [1.2%] of 163 eyes) had cystoid macular edema develop while being treated with latanoprost.
Although latanoprost is an effective ocular-hypotensive agent, the authors' experience with the drug has shown a significant incidence of anterior uveitis and cystoid macular edema. To the authors' knowledge, this is the first study to report the incidence of both cystoid macular edema and anterior uveitis associated with latanoprost therapy. Treating physicians should be aware of these potential complicating side effects of latanoprost.
To determine the safety and efficacy of low-dose methotrexate (MTX) for sarcoid-associated panuveitis.
Retrospective noncomparative case series.
Twenty eyes from 11 patients were analyzed. Eight patients had sarcoidosis. Three patients were clinically suspected of sarcoidosis despite negative laboratory testing. All charts of patients with sarcoidosis and idiopathic uveitis seen by the Duke Uveitis Service from 1989 to 1997 were retrospectively reviewed. Those with sarcoid-associated or sarcoid-suspected panuveitis treated with MTX with a minimum of 6 months of follow-up were studied.
Low-dose MTX was administered to patients weekly and patients were followed with serial ophthalmologic and medical examinations.
Visual acuity, oral and topical corticosteroid requirements, anterior chamber inflammation, and ability to undergo successful cataract extraction were used to measure the efficacy of MTX therapy.
After MTX treatment was initiated, 90% of eyes had preserved or improved visual acuity. Mean initial Snellen visual acuity was 20/62 and mean final acuity was 20/40 (P = 0.044). Of those patients initially requiring oral corticosteroids, the dosage was decreased in 100%, and they were completely discontinued in 86%. The mean initial oral corticosteroid dose was 26.6 mg and the mean final dose was 1.5 mg (P = 0.012). Topical corticosteroids were decreased in 63% of eyes. The mean initial use was once every 1.6 hours, and the mean final use was once every 3.9 hours (P = 0.001). Ninety-five percent of eyes had stabilized or decreased inflammation. The mean initial inflammation score was 1.2, and the mean final score was 0.5 (P = 0.007). Five of six eyes previously unable to have cataract extraction because of uncontrolled inflammation became quiet on MTX and underwent surgery. One hundred percent of these eyes had improved vision after surgery. Side effects were mild and transient or reversible.
Low-dose MTX is an effective and safe adjunct to treat chronic sarcoid-associated panuveitis.
To describe the risks, benefits, and recommended use of the ganciclovir implant for the treatment of human immunodeficiency virus-related cytomegalovirus (CMV) retinitis in the era of potent antiretroviral therapy.
A panel of physicians with expertise in the use of the ganciclovir implant and in the management of CMV retinitis was convened by the International AIDS Society-USA. The panel reviewed and discussed available data, and developed recommendations for the use of the ganciclovir implant, the surgical technique, and related management issues. Recommendations were rated according to the strength and quality of the supporting evidence.
The effect of potent antiretroviral therapy on the immunologic status of patients with human immunodeficiency virus disease has changed the manifestation and course of CMV retinitis in many patients. The clinical management of CMV retinitis and the role of the ganciclovir implant are thus changing. Factors in the decision to choose the ganciclovir implant include the patient's potential for immunologic improvement, location and severity of CMV retinitis, and the risks and costs associated with implantation and concomitant oral ganciclovir therapy.
The ganciclovir implant is safe and effective for the treatment of CMV retinitis. The indications for its use should be modified to account for increased patient survival and the potential for CMV retinitis to be controlled by effective antiretroviral therapy. Optimal use of the ganciclovir implant and discontinuation of therapy in selected patients with improvement in immunity may result in better long-term visual outcomes.
Ashton and Guo are employees of Control Delivery Systems, Inc., and, as such, may have a financial interest in the fluocinolone acetonide device. Drs. Jaffe, Dunn, and Ben-nun do not have a proprietary interest in the device
- Dr
- Lew R Jaffe
- Award Recipient Wasserman
- Drs
Dr. Jaffe is a Lew R. Wasserman Merit Award Recipient. Drs. Ashton and Guo are employees of Control Delivery Systems, Inc., and, as such, may have a financial interest in the fluocinolone acetonide device. Drs. Jaffe, Dunn, and Ben-nun do not have a proprietary interest in the device. Correspondence to Glenn J. Jaffe, MD, Duke University Eye Center, Box 3802, Durham, NC 27710. E-mail: jaffe001@mc.duke.edu. 2024 © 2000 by the American Academy of Ophthalmology ISSN 0161-6420/00/$–see front matter Published by Elsevier Science Inc. PII S0161-6420(00)00466-8 References