Injection intravitreal

The therapeutic utility of systemically administered ASON had been limited by their short plasma half life (sometimes even less than 3 min). This is due to their sensitivity to nuclease digestion. When the first-generation ASON were chemically modified, e.g., by replacing the oxygen in the phosphodiester bond with sulfur (phosphorothiorate) they obtained an increased stability in biological fluids while their antisense effect has been maintained. First-generation agents can be delivered via intravitreal injection, parenterally, by topical cream, enema, and inhaled aerosol. These antisense... 

Liposomes have been studied to improve the ocular availability of drugs after application to the eye or after intravitreal injection. Besides, a liposomal eye drop formulation for the treatment of dry eye symptoms was developed and entered the clinical phase II stage (Guo et al., 1988). 

J. (1985). Ocular toxicity of intravitreally injected liposomal amphotericin B in rhesus monkeys. Am. J. Ophthalmol., 100, 259-263. 

A number of diflFerent animal models of uveitis have been developed) including that induced by organ-specific ocular antigens such as retinal S-antigen, rhodopsin and lens protein (Wacker et al., 1977 Rao et al., 1979). Other models are based on the injection of proteins foreign to the host, such as intravitreal injections of albumin or 7-globulin (Zimmerman and Silverstein, 1959 Kaplan etal., 1979). More recently, a third group of models has been developed based on the injection of inflammatory mediators such as interleukins-1 and 2, and tumour necrosis factor (Bhattacherjee and Henderson, 1987 ... 

Rosenbaum et al., 1988 Samples et al., 1989). Rao (1990) has suggested that the primary inflammatory response in all these models based on intravitreal injection is an acute vitritis rather than uveitis. 

Pegaptanib 0.3 mg is administered as an intravitreous injection every 6 weeks. In clinical studies, patients treated with pegaptanib experienced a slower rate of visual decline than patients treated with a sham injection.28 Vision loss continued to occur in patients and the drug was less effective in the second year of treatment. Long-term efficacy studies are not available yet.27... 

In order to design such an efficient and effective device, one must understand the mechanisms by which drug is transported in the ocular interior. One issue debated in the literature for some time has been the relative importance of transport by passive diffusion versus that facilitated by the flow of fluid in the vitreous (see, e.g., Ref. 226). To predict the geometric distribution even at steady state of drug released from an implant or an intravitreal injection, one must appreciate which of these mechanisms is at work or, as appropriate, their relative balance. 

Elimination from the vitreous occurs by one of two pathways. This can be visualized by injecting fluorescent compounds and examining the concentration distribution in frozen sections obtained after a steady state has been established [230]. If the major route of elimination is by means of the re-tina/choroid, at steady state the lowest concentration would be in the vicinity of the retina. The contours observed in frozen sections of the rabbit eye obtained after intravitreal injection of fluorescein exhibit this pattern, with the highest concentration immediately behind the lens (Fig. 16A). Compounds not chiefly eliminated through the retina exit the vitreous by passive diffusion and enter the posterior aqueous, where they are eliminated by the natural production and outflow of aqueous humor. In such a situation, the contours would be perpendicular to the retina, with the highest concentration towards the rear of the vitreous cavity. This appears to be the case for fluorescently labeled dextran polymer, whose contours decrease in concentration toward the hyaloid membrane (Fig. 16B). 

FDA approved intraocular injections include mio-tics, viscoelastics, and viscoadherents and an antiviral agent for intravitreal injection. The approved intraocular miotics, carbachol (Miostat ) and acetylcholine (Miochol ), are injected into the anterior chamber at the end of cataract surgery to constrict the pupil and allow the iris to cover the implanted intraocular lens. Carbachol is formulated in a BSS vehicle in sterile water for injection at a physiological pH... 

A new antiviral agent, developed for treatment of CMV retinitis, can be administered by intravitreal injection. Formivirsen sodium is a phosphorothioate oligonucleotide that inhibits CMV replication through an antisense mechanism. It is formulated as a sterile and preservative-free solution and supplied in single-use vials (Vitravene ). The product is administered directly into the vitreous cavity posterior to the limbus through a 30-gauge needle. This procedure can be performed on an... 

Administration is by direct injection of 0.05 ml product into the eye (intravitreal injection), initially once every 2 weeks and subsequently once every 4 weeks. Animal studies (rabbits) indicated that the product is cleared from the eye over the course of 7-10 days, with direct nuclease-mediated metabolism representing the primary route of elimination. The most commonly observed side effect is ocular inflammation, which typically occurs in one in every four patients. 

Lucentis contains ranibizumab and is available for intravitreal injection. It is a vascular endothelial growth factor inhibitor indicated for the treatment of neovascular (wet) age-related macular degeneration. Unlike verteporfin, which is used in photodynamic treatment of age-related macular degeneration, ranibizumab does not require activation by local irradiation using non-thermal red light. 

Developed by the US company Isis, Vitravene is used to treat cytomegalovirus (CMV) retinitis in AIDS patients. It is formulated as a sterile solution in WFI (Chapter 3) using a bicarbonate buffer to maintain a final product pH of 8.7. Administration is by direct injection into the eye (intravitreal injection) and each ml of product contains 6.6 mg of active ingredient. 

Pharmacokinetics Minimal systemic absorption following intravitreal injection. 

CMV retinitis Intravitreal injection 330 meg (0.05 ml) every other week for 2 doses, then 330 meg every 4 weeks. 

Dosage form Vitravene is a sterile, aqueous, preservative-free, buffered solution supplied in 0.25 ml single-use vials for intravitreal injection. Each ml of Vitravene solution contains fomivirsen sodium 6.6 mg. 

Recommended dosage and monitoring requirements For the treatment of CMV retinitis in AIDS patients, the recommended dose of Vitravene is 330 pg (0.05 ml) by intravitreal injection for induction, one dose should be injected every other week for two doses for maintenance, after induction, one dose should be given once every 4 weeks after induction. 

Pharmacokinetics No information on human pharmacokinetics is available. In the rabbit model, half-life in the vitreous humor was 62 hours and 79 hours in the retina, while the retinal half-life in monkeys was 78 hours. Systemic exposure to fomivirsen following single or repeated intravitreal injection in monkeys was not quantifiable. 

Parenteral 0.3 mL for intravitreal injection Peginterferon alfa-2a (Pegasys)... 

Parenteral 10 mg/mL for intravitreal injection Rh0(D) immune globulin micro-dose (RhoGam, others)... 

Intravitreal triamcinolone injection is safe and effective for cystoid macular edema caused by uveitis, diabetic maculopathy, and central retinal vein occlusion, and for pseudophakic cystoid macular edema. Potential risks include glaucoma, cataract, retinal detachment, and endophthalmitis. Infectious endophthalmitis is extremely rare when appropriate sterile technique is practised. Seven patients developed a clinical picture simulating endophthalmitis after intravitreal injection of triamcinolone (71). The authors believed that this effect was a toxic reaction to the injected material and explained that the differential diagnosis of infectious endophthalmitis in eyes that have been injected with triamcinolone under sterile conditions includes a sterile toxic endophthalmitis that requires careful monitoring, perhaps every 8-12 hours, in order to determine whether the inflammation is worsening or improving. Resolution occurs spontaneously, and in the absence of eye pain unnecessary intervention can be avoided. 

Hypopyon associated with non-infectious endophthalmitis after intravitreal injection of triamcinolone has been described previously (72). Pseudohypopyon and sterile endophthalmitis after intravitreal injection of triamcinolone for pseudophakic cystoid macular edema has been reported (73). 

Kamei, M., K. Misono, and H. Lewis. 1999. A study of the ability of tissue plasminogen activator to diffuse into the subretinal space after intravitreal injection in rabbits. Am J Ophthalmol 128 739. 

A number of antibiotics, including gentamicin, cephazolin, ticarcillin, amikacin, and vancomycin have been successfully delivered into the vitreous of rabbit eyes (Table 26.2). Barza et al. [74] further investigated the efficacy of transscleral iontophoresis of gentamicin for the treatment of Pseudomonas endophthalmitis in rabbits. They found that two sessions of iontophoresis in addition to an intravitreal injection of gentamicin resulted in a significantly lower number of bacterial colonies in the vitreous than by the injection alone. 

Fomivirsen Intravitreal injection CMV retinitis treatment (induction or maintenance) Induction 330 vg every 14 days Maintenance 330 Mg every 4 weeks... 

ASOs are synthesized as complex mixtures of diastereomers. In the solid state, they are amorphous, electrostatic, hygroscopic solids with low-bulk densities, possessing very high surface areas, and poorly defined or no melting points. Their good chemical stability allows them to be stored as lyophilized or spray-dried powders, or as concentrated, sterile solutions. For example, the 21-mer ASO Vitrave-ne (fomivirsen sodium intravitreal injectable) is approved in the USA for a storage condition from 2 to 25 °C [2]. 

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