Thursday, January 11, 2018

SUSTAINED RELEASE MEDICATIONS IN GLAUCOMA


Compliance to anti-glaucoma medications remains a major limiting factor in the management of glaucoma. With old age come physical difficulties in instilling medications, dementia leads to forgetfulness of the doses and the financial constraints in buying medications indefinitely puts a strain on the pocket of old pensioners. In order to overcome the factor of non-compliance to anti-glaucoma medications, sustained release drug delivery systems are being investigated. 


These long-acting or enhanced delivery systems can be broadly divided into EXTERNAL and INTERNAL platforms, depending upon their location with respect to the coats of the eyeball.


EXTERNAL PLATFORMS:


1. PUNCTAL PLUGS= Drug-infused plugs which can be inserted into the punctum are undergoing clinical trials. These include the Ocular Therapeutix’s Travoprost (OTX-TP) and the Mati Therapeutic’s Latanoprost plugs. The former is cylindrical while the latter is arrow shaped to prevent inadvertent slippage into the canaliculi. The OTX-TP is expected to provide sustained drug delivery for 2-3 months. 


OTX-TP

Mati Therapeutics punctal plug

With the Mati Therapeutic’s plug, IOP reportedly dropped by 6 mmHg after 1 week. 


Side effects of plugs include falling out or intra-canalicular migration, local skin darkening near the medial canthus and epiphora due to the plug blocking the punctum.


2. RINGS= A ring, containing Bimatoprost, which fits into the superior and inferior fornices is being developed by Allergan. The retention rate of the ring is reportedly around 90% at 6 months and the efficacy lasts for 4-6 months. The loss of efficacy is presumably due to the elution of the drug with time and the blockage of receptors due to continuous exposure to the drug. When the ring was re-inserted after 6 months of initial use, the same effectiveness as in the first insertion was not seen, probably due to the down-regulation of the receptors.




3. PERIOCULAR INJECTION= A subconjunctival bioerodable pellet containing Latanoprost is being developed. Known as the Durasert, the 3 mm implant is injected using a 27-gauge needle. Pfizer and pSivida are conducting a Phase I/II safety and efficacy trial of the Durasert.




4. SUBCONJUNCTIVAL INJECTION= Natarajan JV and colleagues reported Latanoprost incorporated into LUVs (Large Unilamellar Vesicles) derived from the liposome of DPPC (di-palmitoyl-phosphatidyl-choline) by a film hydration technique, and injected subconjunctivally. The IOP lowering efficacy of this vehicle was sustained upto 50 days.




https://www.sciencedirect.com/science/article/pii/S0168365914003320 


5. CONTACT LENSES= (a) Latanoprost eluting low dose contact lenses (CLLO) and high dose contact lenses (CLHI) have been produced by encapsulating a thin latanoprost-polymer film within the methafilcon hydrogel lathed into a contact lens. As reported by Ciolino and colleagues in Ophthalmology journal, CLLO reduced IOP by 6.3+/-1.0 (at day 3), 6.7+/- 0.3 (at day 5) and 6.7+/-0.3 (at day 8). The CLHI reduced IOP by 10.5+/-1.4 (at day 3), 11.1+/-4.0 (day 5) and 10.0+/-2.5 (day 8). Topical Latanoprost reduced IOP by 5.4+/-1.0 mmHg on day 3 and 6.6+/-1.3 mmHg on day 5. Thus, sustained delivery of Latanoprost by contact lens was found to be atleast as effective as the topical application. (b) Hiratani and Alvarez-Lorenzo have reported the usage of soft contact lenses consisting of polymers of N,N-diethylacrylamid and methacrylic acid which appear to deliver timolol for approximately 24 hours.

 https://www.ncbi.nlm.nih.gov/pubmed/27586444

https://www.ncbi.nlm.nih.gov/pubmed/12363448 


6. TOPICAL OPHTHALMIC DRUG DELIVERY DEVICE (TODDD) = This device developed by Amorphex Therapeutics has combined polymers which allow sustained release of Timolol. The device is put under the upperlid, where it floats over the tear film. It has a corneal relief curve which prevents it from riding over onto the cornea. IOP was found to be reduced by 16-22%. The company is planning Phase I trials for the TODDD. The device will  probably be effective for 90 days.




INTERNAL PLATFORMS:


1. Allergan’s bimatoprost sustained-release implant, which can be injected into the anterior chamber, is undergoing Phase III trials. In Phase II trials it reduced IOP in 92% patients at 4 months and in 71% at 6 months. The pressure lowering was by 8-10 mmHg at week 2, but by week 26 the IOP lowering was by 6-8 mmHg. The advantage of such implants is that there is no risk of dislodgement. 






2. ENV515 (Envisia): This intracameral implant uses Travoprost. It uses a biodegradable polymer drug delivery system. In Phase I trials IOP reduced an average of 35% (6.4+/-0.6 mmHg) over 8 months, but returned to baseline at 9 months. In Phase IIa clinical trials IOP was reduced by 28% (6.7 mmHg) at day 25, which was comparable with instillation of Travatan Z once daily in the other eye. The only side effect noted was transient hyperemia.




3. GrayBug is developing a microparticle technology originally created at the Wilmer Eye Institute. 3 possible agents: a single IOP lowering compound; a dual-action IOP-lowering compound and another IOP-lowering agent with neuroprotective properties, are being developed. The agents will be injected intravitreally or subconjunctivally. The implant would be absorbed over a 6-month period.

http://graybug.com/pipeline/gb-201-202-203-glaucoma/ 


4. Clearside Biomedical and Santen are developing a supraciliary drug delivery system using Clearsides’ microinjector and Santen’s sustained release formulations. Sulprostone and Brimonidine were tested with the delivery system and decreased IOP significantly compared to their topical counterparts. In rabbit eyes, a single injection of Brimonidine reduced IOP by 6 mmHg. However, the effect tapered off after a month.

https://www.businesswire.com/news/home/20150504005229/en/Clearside-Biomedical-Santen-Announce-Research-Collaboration-Glaucoma 


5. Ohr Pharmaceuticals is developing injectable micro- or nano-articles using Latanoprost. The particles can potentially be injected within or around the eye. Adnexal adverse effects do not occur with this agent. However, there is risk of toxicity, damage to intraocular structures and need for lifelong procedures to ensure sustained lowering of IOP.

6. Icon Bioscience is developing a biodegradable injectable implant to deliver Latanoprost. The IBI-60089 is injected intracamerally through a 30G needle.

 http://iconbioscience.com/pipeline/


7. Euclid Systems is developing 2 collagen based systems to provide sustained release of Latanoprost. The first is an injectable insitu gelling collagen solution and the second a 2mm x 4mm collagen wafer implanted over the sclera. The latter has shown the release of Latanoprost to last upto 180 days.

8. Replenish has developed the Ophthalmic Micropump which is implanted over the sclera. The wireless connected and programmable system dispenses nano-liter sized doses of drugs, which can last upto 12 months. Once the medication is exhausted, the device can be refilled with a 31G needle. 





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Thursday, January 4, 2018

UVEITIC GLAUCOMA


The association of uveitis and glaucoma was first described by Joseph Beer.


The incidence of glaucoma associated with uveitis in both adults and children is nearly the same, i.e. 5-20%. However, the visual prognosis in children is poorer compared to adults.


When IOP is elevated for a short period and it does not induce either optic nerve or visual field damage, the term “uveitis-related ocular hypertension” may be used.


The term “uveitic glaucoma” should ideally be used when uveitis is associated with elevated IOP, glaucomatous optic nerve damage, and/or glaucomatous visual field defects.


Mutton-fat keratic precipitates (usually found in Arlt’s triangle), are present in:

                                                               i.      Tuberculosis

                                                             ii.      Sarcoidosis

                                                            iii.      Sympathetic ophthalmia

                                                           iv.      Phacoanaphylactic uveitis



Not all cases of uveitis are associated with high IOP. The IOP can be low, normal or high depending upon the cause.


HLA-B27 positive individuals have more severe uveitis compared to HLA-B27 negative individuals.


Certain anti-glaucoma medications such as Brimonidine can cause uveitis. Whether prostaglandin analogues can also lead to such a situation is not known.


Dynamic gonioscopy is a useful test to perform in order to differentiate between appositional versus synechial closure. The latter being commonly seen in glaucoma associated with uveitis.


Posterior segment findings in uveitis include= vascular sheathing, perivascular exudates, cystoid macular edema, retinitis, choroidal infiltrates, retinal detachment, pigmented or atrophic scars and pars plana exudates (snowbanking) and glaucomatous optic nerve head changes.


T-cells lay a major role in the pathogenesis of uveitis. They are the most abundant cell type in uvea, retina, aqueous and vitreous in patients with uveitis.


In normal eyes, the protein content in aqueous humor is approximately 1/100th of that in serum. However, during inflammation the protein content of the aqueous humor increases. It is a non-specific transudation due to increased permeability of the blood-aqueous-barrier. The probable sites of protein leakage include: disrupted ciliary epithelium and proliferating blood vessels.


Fluorescein angiography of iris reveals hypoperfusion and microneovascular changes suggesting another site from where protein leakage could occur.


Prostaglandins have been found to be increased in uveitis but they are not presumed to play a role in uveitis-induced ocular hypertension.


Inflammatory mediators (Cytokines) and toxic agents (Oxygen Free Radicals) also play a role. Cytokines are soluble polypeptides which play a critical role in the immune response by regulating leucocyte interactions. They are secreted principally by monocytes/macrophages and lymphocytes, although any cell which participates in the immune response may secrete them (e.g. neutrophils, endothelial cells and fibroblasts). Cytokines (IL- 1, IL-2 and Tumor Necrosis Factor [TNF]) may influence IOP by increasing the inflammation by stimulating neovascularization and by having a direct effect on aqueous humor dynamics. Tissue Growth Factor (TGFβ-2) a potent immunosuppressive normally present in the eye is decreased or absent in the aqueous and vitreous of eyes with various inflammatory disorders.


Oxygen Free Radicals are released by macrophages and Polymorphonuclear Neutrophils (PMNs). PMNs and macrophages undergo a “respiratory burst” which is characterized by increased consumption of oxygen, increased utilization of glucose via the Hexose MonoPhosphate Shunt pathway and release of oxygen metabolites. 


It has been proposed that the superoxide radical itself is poorly reactive in aqueous solution and the tissue damaging effects are more from reactive secondary products e.g. Hydrogen Peroxide, Hypochlorous Acid and Hydroxyl radicals.


Damage to the trabecular meshwork or angle structures by OFRs may cause a rise in IOP.


Posterior synechiae occur more commonly in granulomatous than non-granulomatous uveitis.


Peripheral anterior synechiae (PAS) may form secondary to inflammation, neovascularization or iris bombe.


Pseudo-exfoliative glaucoma may induce more inflammation than primary open angle glaucoma (POAG) because of the very labile blood aqueous barrier balance.


Secondary open angle glaucoma associated with uveitis due to mechanical blockage or dysfunction of outflow pathway, results in decreased outflow facility. The level of IOP will depend upon the rate of aqueous humor production by the ciliary body.


Trabeculitis may also contribute to a rise in IOP. This is characterized by inflammatory precipitates on the trabecular meshwork. Since trabeculitis is usually not associated with concomitant inflammation of the secretory ciliary epithelium, aqueous production is normal. The elevated IOP is purely as a result of reduced aqueous outflow.


Swelling or dysfunction of the trabecular beams or endothelial cells can cause a reduction in diameter of trabecular pores.


Steroid-induced glaucoma:

b.      IOP usually rises 2 or more weeks after initiating steroid therapy. (But may occur anytime)

c.       Steroids can be instilled in the opposite eye to look for steroid responsiveness.

d.      Steroids increase IOP by reducing aqueous outflow. Many theories have been proposed to explain this phenomenon, including: accumulation of glycosaminoglycans in the trabecular meshwork (by inhibiting their catabolism; inhibition of phagocytosis of foreign material by trabecular endothelial cells; inhibition of synthesis of prostaglandins (PGE2 and PGF2, which increase the outflow facility).

e.      Management:

·         Taper steroids

·         Change to lower concentration or a drug with lesser tendency to elevate IOP e.g. Medrysone or fluoromethalone.

·         Rimexolone has maximal anti-inflammatory effects and minimal effects on IOP elevation. (1% suspension as effective as 1% Prednisolone in management of uveitis. Prednisolone 1% is 1.7-8 times more likely to produce IOP elevation). In mild cases the steroid can be replaced by NSAIDs. While in severe cases it can be replaced with immunosuppressives. In depot steroid injections (Triamcinolone), the IOP may remain elevated for 18 months or more. This often requires surgical removal of depot-steroid or filtration surgery.


Management of uveitic glaucomas:


(A)   Medical therapy:

Mydriatic-cycloplegic agents.

Agents which reduce IOP e.g. beta-blockers.

Adrenergic agonists= epinephrine, dipivefrine, apraclonidine.

Carbonic anhydrase inhibitors.

Hyper-osmotic agents

Miotics should be avoided as they potentiate posterior synechiae and pupillary membrane formation; cause discomfort by aggravating ciliary spasm and increase inflammation by increasing breakdown of blood-aqueous barrier and accelerating release of enzymes from PMNs.


(B) Surgical therapy:

i. Uveitis is associated with cellular changes in conjunctiva including increased numbers of fibroblasts, lymphocytes and macrophages, which are important causes of filtering surgery failure. Therefore, the eye should be quite for 3 months prior to surgery and operated under steroid cover. In certain patients topical prednisolone 1% eyedrops hourly and Oral prednisolone 40mg per day can be instituted 1 week prior to surgery. At the time of surgery a depot of corticosteroid should be injected sub-conjunctivally far from the bleb.

ii. Surgical iridectomy can be done in those eyes, where laser PI is not successful. However, iridectomies are only effective in the eyes which have PAS involving <75% of the angle. It has fewer propensities for closure, but induces more inflammation compared to laser procedures.

iii. In case the iridotomy is not successful, then filtering surgeries or destruction of the ciliary body can be done.


(C) Laser procedures:

In case of angle closure, laser iridotomy can be done. Combined Argon and Nd:YAG lasers are more effective in thicker irides. To prevent inflammation, topical steroids can be instilled every 5 minutes for 30-60 minutes and then every 6 hours for 1-2 weeks.