|PRACTICE CHANGING CONTINUING EDUCATION: CLINICS IN OPHTHALMOLOGY
|Year : 2015 | Volume
| Issue : 3 | Page : 126-132
Prostaglandin analogs in glaucoma
Harinder Singh Sethi1, Munish Dhawan2, Mayuresh Pramod Naik1, Vishnu Swarup Gupta1
1 Department of Ophthalmology, VMMC and Safdarjung Hospital, New Delhi, India
2 Department of Ophthalmology, Guru Gobind Singh Medical College and Hospital, Faridkot, Punjab, India
|Date of Web Publication||2-May-2016|
Mayuresh Pramod Naik
Room No. 430 of Eye OPD, 4th Floor of OPD Building, VMMC and Safdarjung Hospital, Ansari Nagar, Ring Road, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
Glaucomatous visual changes and defects are almost irreversible, with the visual field changes of glaucoma being noticed by the patient after significant disease progression due to a relative lack of alerting symptoms. Reduction of elevated intraocular pressure (IOP) is the only as yet proven approach to protect against visual field loss in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). When they first entered the ophthalmic market about 10 years ago, prostaglandins were viewed skeptically as a potential first-line therapy for glaucoma patients. Yet in less than a decade, glaucoma specialists' preferences have changed, with most reporting that they prefer prostaglandins over beta blockers as their patients' initial medication. Latanoprost has truly withstood the test of time and has indeed proved to be one of the best anti-glaucoma medications when used as monotherapy or as adjunctive therapy. Bimatoprost 0.01% has a similar overall safety profile, a favorable hyperemia profile, and less overall discontinuation compared with Bimatoprost 0.03%. In lieu of its poor efficacy, Unoprostone has lost its hold in the anti-glaucoma palate. Travatan Z (travoprost) is a new formulation of Travatan solution in which benzalkonium chloride is replaced with Sofzia, a robust ionic buffered preservative system that is gentle to the ocular surface. Tafluprost, the newest addition to the prostaglandin brigade, is a fluorinated analogue of prostaglandin-F 2α and is available as a sterile ophthalmic solution of 0.0015% (0.015 mg/ml) being approved by the US-FDA on 10th February, 2012. A new futuristic glaucoma therapeutic management paradigm where clinical success is no longer simply measured by achieved level of intraocular pressure control but also long-term preservation of visual function and patient's quality of life is expected to dramatically improve upon current treatment algorithms for ocular hypertension and glaucoma.
Keywords: Glaucoma, prostaglandin analogs, tafluprost
|How to cite this article:|
Sethi HS, Dhawan M, Naik MP, Gupta VS. Prostaglandin analogs in glaucoma. Astrocyte 2015;2:126-32
| Introduction|| |
Glaucomatous visual changes and defects are almost irreversible, with the visual field changes of glaucoma being noticed by the patient after significant disease progression due to relative lack of alerting symptoms. Reduction of elevated intraocular pressure (IOP) is the only as yet proven approach to protect against visual field loss in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT)., After making an accurate diagnosis, assessment of the stage of the disease and the risk factors for disease progression, both influence how aggressive the ophthalmologist should be to achieve target IOP range to minimize the progression of glaucomatous optic atrophy.
Topical medications to treat glaucoma were first used in the 1870s when pilocarpine and physostigmine were introduced for the 1st time. Subsequently, other categories of drugs were added to armamentarium. Topical drugs used in glaucoma include α-agonists wherein nonselective was epinephrine and dipivefrin while α2-selective was brimonidine and apraclonidine; β-blockers, namely timolol, levobunolol, betaxolol, carteolol, and metipranolol; miotics, i.e., direct parasympathomimetics was pilocarpine; carbonic anhydrase inhibitors include dorzolamide and brinzolamide while prostaglandin (PG) analogs are latanoprost, travoprost, unoprostone, bimatoprost, and tafluprost–being the latest addition to the PG bandwagon. Systemic ones are carbonic anhydrase inhibitors–acetazolamide, methazolamide, and dichlorphenamide–and hyperosmotic agents–mannitol and glycerol. Miscellaneous drugs include forskolin, ethacrynic acid, steroid antagonists, cannabinoids, angiotensin-converting enzyme inhibitors, atrial natriuretic peptide, and neuroprotective agents. If the drugs were to be classified according to their mechanism of action, then drugs that decrease aqueous production include α-agonists and β-blockers whereas miotics increase trabecular outflow and PG analogs increase uveoscleral outflow.
When they first entered the ophthalmic market about 10 years ago, PG s were viewed skeptically as a potential first-line therapy for glaucoma patients. Yet in less than a decade, glaucoma specialists' preferences have changed, with most reporting that they prefer PGs over β-blockers as their patients' initial medication. Even though β-blockers have reigned the antiglaucoma therapy since time eternity, a major reason why ophthalmologists prefer PGs now is that they do not have the same systemic side effects, namely the ability to trigger asthma attacks, fainting episodes, and cause central nervous system side effects such as depression and decreased sexual function.
| Latanoprost|| |
Latanoprost was developed by Carl B. Camras and his research adviser László Z. Bitó at Columbia University in 1996; after its Food and Drug Administration (FDA) approval on July 5, 1996, Latanoprost was the first clinically developed practical PG for the treatment of glaucoma. Being well tolerated with no detectable systemic side effects, it has been used as monotherapy and in combination with other antiglaucoma agents.
It is a highly lipophilic 17-phenyl substituted PGF2α Fluoroprostanoid receptor (FP receptor) - isopropyl ester prodrug. Latanoprost is a prostanoid selective FP receptor agonist. Reduction of IOP starts approximately 3–4 h after administration and maximum effect is reached after 8–12 h. It has a duration of action ranging from 20 to 24 h.,
Latanoprost acts by enhancing uveoscleral outflow rather than altering the conventional trabeculo-canalicular aqueous outflow. Latanoprost regulates uveosclearal outflow by matrix metallo proteinase (MMP)-mediated alterations in ciliary muscle extracellular matrix metabolism (ECM). Exposure of ciliary smooth muscle cells to latanoprost leads to expression of MMP-I through increased transcription of the MMP-I gene. Having undergone enzymatic hydrolysis in cornea, it gets activated to the acid of latanoprost. When the drug passes into the anterior chamber, it interacts with the receptor and then drug-receptor complex interacts with nuclear genetic material. This transcription of mRNA and translation of proteins ultimately causes biosynthesis of MMPs which alters the collagens with the uveoscleral pathway. Gene transcription offers the potential of more specific regulation of the uveoscleral outflow pathway.,
The only possible contraindication to latanoprost is any known hypersensitivity to latanoprost or any other ingredient in this product.
Latanoprost is available as 0.005% topical ophthalmic solution (Xalatan eye drops) to be stored in refrigerator at 2–8°C when unopened. Once opened it may be stored at room temperature up to 25°C for 6 weeks. Usual dosage is to instill one drop (containing 15 mg) in the affected eyes, once daily, preferably in the evening. When latanoprost is used concomitantly with other antiglaucoma drugs to lower intraocular pressure (lOP), they should be administered 5 min apart. Recently in 2012, topical latanoprost (0.005%) and timolol (0.5%) combined ophthalmic solution (xalacom) has been launched commercially. The salient features for this new combination reported are better treatment compliance, reduced washout associated with the use of sequential eye drops, and improved long-term lOP control in patients (17–34%) who proved inadequately controlled on either loose or fixed dose multiple drop regimes.,
Patients should be informed in advance about the possibility of changes in iris color as latanoprost may gradually increase the amount of brown pigment in the iris by increasing the number of melanosomes (pigment granules). The change occurs slowly for several months to years and resultant color change may be permanent.
Some 3–10% patients have shown iris pigmentation and cystoid macular edema. Other local side effects reported on long-term use include mild conjunctival hyperemia, punctate corneal erosions, lengthening and thickening of eyelashes, blurred vision, burning and stinging sensation, and itching and punctate epithelial keratopathy. Less than 1% of patients treated with latanoprost require discontinuation of therapy due to conjunctival hyperemia. The most common systemic adverse effects seen are upper respiratory tract infection, cold, flu, pain in the muscles, joint, back, chest pain, angina pectoris, rashes, and allergic reaction. However, the incidence of adverse effects is very low.,
| Unoprostone|| |
The next drug in antiglaucoma armor, unoprostone isopropylate (rescula) is PGF2α - analog of PG group. Even though this compound was first developed in Japan in 1994 for use in open-angle glaucoma or OHT, it became available for clinical use in the United States after its US-FDA approval on August 03, 2000. It thus became the first docosanoid (22-carbon-molecule) derivative for glaucoma treatment.,
Oculohypotensive effect is similar to or slightly inferior to that of timolol 0.5%. It has also been seen in some studies to increase the optic nerve head blood flow. It has an additive efficacy with latanoprost and can safely improve the diurnal curve characteristics in patients who continue to have an elevated lOP on latanoprost 0.005% alone.
Similar to latanoprost, unoprostone lowers IOP by increasing uveoscleral outflow and without affecting aqueous humor production.
Unoprostone is available as 0.15% topical ophthalmic solution. Recommended dosage is to instill one drop in the affected eye twice a day. It can be given continuously for a long period and it maintains lower IOP even over a longer period of 12 months.
Ocular adverse effects include iris pigmentation, conjunctival hyperemia, ocular irritation, burning and stinging sensation and ocular pruritus.
| Bimatoprost|| |
After the successful use of latanoprost and the debacle of unoprostone, research led to the development of bimatoprost. Also known as AGN 192024, it was approved for clinical use by the US-FDA on March 16, 2001. It is pharmacologically unique compound of PG group which appears to mimic the prostamides. Prostamides are the newest members of the fatty acid amide family, which are potent ocular hypotensive agents. Its chemical structure differs from PGF2α and the other PG analogs with an amide ethyl group at the C-1 position.
Bimatoprost is unique in its function and binding studies at recombinant and natural receptors. Bimatoprost does not require conversion to an active metabolite to exert potent pharmacological activity. It is not only stable in solution but also does not undergo facile hydrolytic conversion. Chemically bimatoprost is related to prostamide-F, a newly discovered, naturally occurring substance, i.e., biosynthesized from anandamide in a pathway that includes the enzyme cyclooxygenase-2. It does not bind to the PGFP receptor.
Bimatoprost mildly stimulates the aqueous humor outflow both during day and night. Enhancement of uveoscleral outflow is the primary mechanism of action of latanoprost, which is partly responsible for the ocular hypotensive effect of bimatoprost. However, its primary ocular hypotensive action is due to reduction in tonographic resistance to outflow. Thus bimatoprost enhances the pressure sensitive outflow pathway. Reduction of tonographic resistance to aqueous humor outflow reduces steady-state lOP which is beneficial for the treatment of glaucoma. In addition, reduction of resistance allows the eye to recover more quickly from transient lOP elevations.,
Bimatoprost is contraindicated in hypersensitivity to prostamides or any other ingredient in the product.
It is available as 0.03% topical ophthalmic solution. Recommended dosage is to instill one drop in the affected eye once a day preferably at bedtime. It does not require cold chain maintenance.
Adverse effects include iris pigmentation (by increasing the amount of brown pigmentation of the iris due to increase in pigment granules in melanocytes), conjunctival hyperemia, hypertrichosis, burning and stinging sensation, ocular pruritus, ocular pain, eyelid edema, and foreign body sensation. Systemic side effects include nausea, abdominal pain, dizziness, and sinusitis. Bimatoprost is generally not recommended for pregnant, lactating mother, and children.,
| Travoprost|| |
Travoprost (travatan), also known as AL-6221, is another antiglaucoma drug of PG group. It was approved for clinical use on the same day as bimatoprost, i.e. March 16, 2001. It has highly selective affinity for FP receptors and is equally effective to latanoprost and bimatoprost in lowering IOP in cases of POAG or OHT. Commercially it is available as 0.015% topical ophthalmic solution in 5 mL plastic bottle.
Recommended dosage is to instill one drop in the affected eye once a day. It does not require cold chain maintenance. Ocular adverse effects reported are ocular hyperemia, iris pigmentation, decreased visual acuity, eye discomfort, foreign body sensation, ocular pain, and ocular pruritus.
| Tafluprost|| |
Tafluprost, the newest addition to the PG brigade, is a fluorinated analog of PGF2α and is available as a sterile ophthalmic solution of 0.0015% (0.015 mg/mL) with a pH range 5.5–6.7. Tafluprost is specific for FP prostanoid receptors, although some studies have even reported secondary stimulation of EP3 receptors through FP receptors. Tafluprost, like other PGs, thus acts via remodeling of the ECM of the ciliary muscle, relaxation of the ciliary muscle, and changes in cell shape by cytoskeletal alteration. FP receptors exist in two forms, namely type A (full-length receptor) and a type B (splice variant) both of which coupled to the phospholipase C – inositol pathway. The molecular signal transduction cascade leads to induction of the nuclear transcription factor and c-FOS. The c-FOS transcription factor binds to activator protein-1 transcription regulatory element in the promoter of certain gene classes, one of which is the MMP family. The PG-mediated increase in certain MMP correlates with reduction in collagen molecules within the uveoscleral outflow pathways.,
Topical tafluprost solution 0.0015% was approved by the US-FDA for the treatment of POAG and OHT on February 10, 2012. It is now available in the Indian market as “TAFLUMA” eye drops and administered topically as one drop daily to the eye. Patients should be advised not to exceed once daily dosing since more frequent administration may decrease the IOP-lowering efficacy of tafluprost.
Following instillation, tafluprost, being an ester prodrug, is absorbed through the cornea and is hydrolyzed to the biologically active acid metabolite, tafluprost acid. The acid metabolite is further metabolized via fatty acid β-oxidation and phase II conjugation. Following instillation of one drop of 0.0015% solution once daily into each eye of healthy volunteers, the plasma concentrations of tafluprost acid peaked (Cmax) at a median time of 10 min on both days 1 and 8. The mean plasma Cmax values of tafluprost acid were 26 and 27 pg/mL on days 1 and 8, respectively. Mean plasma tafluprost acid concentrations were below the limit of quantification of most of sensitive bioanalytical assays (10 pg/mL) at 30 min following topical ocular administration of tafluprost 0.0015% ophthalmic solution.
The issue of effect of storage temperature has been raised with all topical PG analogs because one study reported that latanoprost exhibits thermal and ultraviolet instability. This raised issues related to chemical stability of the molecule and the role of the composition of the dispensing system on the bioavailability of the drug. A comparative study with the other agents in this drug class has not been reported. Yet unopened vials may be stored refrigerated at 2–8°C (36–46°F). After the vial is opened, the vial may be stored at room temperature 20–25°C (68–77°F) protected from moisture and any such opened vials may be discarded after 28 days.,
The most common adverse reaction observed in patients treated with topical tafluprost 0.0015% was conjunctival hyperemia which was reported in a range of 4–20% of patients. Ocular adverse reactions reported at an incidence of ≥2% in these above clinical trials included ocular stinging/irritation (7%), ocular pruritus including allergic conjunctivitis (5%), cataract (3%), dry eye (3%), ocular pain (3%), eyelash darkening (2%), growth of eyelashes (2%), and vision blurred (2%).,
Tafluprost ophthalmic solution has been reported to cause changes in pigmented tissues, the most frequently reported changes being increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as tafluprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of tafluprost, pigmentation of the iris is likely to be permanent, whereas pigmentation of the periorbital tissue and eyelash changes has been reported to be reversible in some patients. Typically, the brown pigmentation around the pupil spreads concentrically toward the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. Topical tafluprost may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, color, thickness, shape, and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment.,
Topical tafluprost should be used with caution in patients with active intraocular inflammation (e.g., iritis/uveitis) because the inflammation may be exacerbated. Macular edema, including cystoid macular edema, has been reported during treatment with PGF2α analogs and hence topical tafluprost should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.,
Tafluprost is a “Category C” drug. Embryo-fetal developmental studies in rats and rabbits suggested teratogenicity of tafluprost by increasing postimplantation losses and reductions in fetal body weights in rats. Tafluprost also increased the incidence of vertebral skeletal abnormalities in rats as well as the incidence of the skull, brain, and spine malformations in rabbits. In rats, there were no adverse effects on embryo-fetal development at a dose of 3 µg/kg/day corresponding to maternal plasma levels of tafluprost acid that were 343 times the maximum clinical exposure based on Cmax. In rabbits, effects were seen at a tafluprost dose of 0.03 µg/kg/day corresponding to maternal plasma levels of tafluprost acid during organogenesis that were approximately 5 times higher than the maximum clinical exposure based on Cmax. At the no-effect dose in rabbits (0.01 µg/kg/day), maternal plasma levels of tafluprost acid were below the lower level of quantification of most of sensitive assays (20 pg/mL). In a pre- and post-natal development study in rats, increased mortality of newborns, decreased body weights, and delayed pinna unfolding were observed in offsprings. The no-observed adverse effect level was at a tafluprost intravenous dose of 0.3 µg/kg/day which is >3 times the maximum recommended clinical dose based on body surface area comparison. There are no adequate and well-controlled studies in pregnant women. Although animal reproduction studies are not always predictive of human response, tafluprost should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Women of childbearing age/potential should have adequate contraceptive measures in place.,
A study in lactating rats demonstrated that radiolabeled tafluprost and its metabolites were excreted in milk. It is not known whether this drug or its metabolites are excreted in human milk. Nevertheless, caution should be exercised when tafluprost is administered to a nursing woman.,
Use in pediatric patients is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use.,
Patients should be advised that if they develop a new ocular condition (e.g., trauma or infection), experience a sudden decrease in visual acuity, have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their ophthalmologist's advice concerning the continued use of tafluprost.,
| Comparative Studies|| |
In a meta-analysis of randomized controlled trials comparing latanoprost 0.005% with timolol 0.5% in the treatment of patients with open-angle glaucoma or OHT, it was suggested that latanoprost is more effective than timolol in lowering IOP.
In yet another similar meta-analysis comparing latanoprost 0.005% with brimonidine 0.2%, similar results were obtained. Fixed drug combinations of latanoprost 0.005% and timolol 0.5% were found to reduce IOP much greater than that reduced by latanoprost or timolol alone., In fact, latanoprost proved not only to be better tolerated but also to have significantly greater efficacy in lowering diurnal mean IOP than combined dorzolamide 2% and timolol 0.5% in patients with IOP insufficiently controlled by timolol alone.
Bimatoprost 0.03% was associated with significantly greater efficacy in lowering morning IOP than latanoprost 0.005%. Bimatoprost 0.03% once daily was safe, better tolerated, and statistically superior to timolol 0.5% twice daily in lowering IOP in patients with ocular hypertension or glaucoma. Bimatoprost given once daily consistently provided IOP reductions approximately 2–3 mmHg greater than those provided by timolol. In individuals with glaucoma or OHT, uncontrolled on a topical β-blocker alone, bimatoprost lowered IOP more consistently than did combined timolol and dorzolamide. Bimatoprost 0.03%/timolol 0.5% fixed drug dosage combination also provided statistically significant greater reduction in IOP than latanoprost 0.005%/timolol 0.5%. However, the combination of bimatoprost and latanoprost in POAG increases the IOP and should not be considered a therapeutic option.
Unoprostone 0.015% twice daily was significantly less effective in reducing IOP compared with latanoprost once daily after 1 month of treatment in patients with POAG and OHT. However, unoprostone isopropyl can safely improve the diurnal curve characteristics in patients who continue to have an elevated pressure on latanoprost 0.005% alone. The hypotensive effects of unoprostone do persist throughout the day but it was suggested that these effects become weaker at night and early morning, thus nullifying the diurnal pressure control when it is most needed.
While most studies unanimously proved that travoprost 0.004% and 0.015% was significantly superior to timolol,,, some studies concluded it to be better than latanoprost  and bimatoprost while yet others claimed that it was equally effective., In fact, when varying concentrations of travoprost were compared with timolol, it was found that significant IOP reductions were found in the travoprost 0.004% group as against the travoprost 0.0015% group. Promising results were obtained with travoprost 0.015%–timolol 0.5% fixed drug dosage combination once daily regimens.
A 12-week, randomized, parallel-group study conducted at 45 US sites to compare safety and efficacy of latanoprost 0.005%, bimatoprost 0.03%, and travoprost 0.015% proved that all the three PG analogs were comparable in reducing IOP, but latanoprost was associated with better ocular tolerability.
Studies with tafluprost 0.0015% have reported an average decrease of IOP of about 25–28% from mean baselines IOPs in about 6–12 weeks when used as monotherapy and similar values when used as adjunctive therapy. A randomized control trial studying the long-term efficacy and safety of tafluprost 0.0015% versus latanoprost 0.005% in open-angle glaucoma and OHT reported that the IOP-lowering effect of tafluprost was noninferior to latanoprost, the noninferiority limit being 1.5 mmHg. A similar randomized control trial of tafluprost 0.0015% versus timolol 0.5% proved the noninferiority of tafluprost in American and European (German) populations within similar limits. Another randomized control trial to investigate the efficacy and safety of tafluprost 0.0015% as an adjunctive therapy to timolol 0.5% in patients with open-angle glaucoma or OHT, uncontrolled by topical timolol 0.5% monotherapy in European (Russian) population reported that reductions in IOP were seen in both groups and were consistently more pronounced with tafluprost.
| Present Scenario|| |
Latanoprost has truly withstood the test of time and has indeed proved to be one of the best antiglaucoma medications when used as monotherapy or as adjunctive therapy. It is not only safe and efficacious but also has the best ocular tolerability profile among the available PG analogs.
Even though bimatoprost still plays a role in the treatment of glaucoma, considering its side-effect profile, on December 05, 2008, the FDA Dermatologic and Ophthalmic Drugs Advisory Committee voted to approve bimatoprost for the cosmetic use of darkening and lengthening eyelashes in hypotrichosis. However, the FDA approval is for purely cosmetic purposes., In August 2010, US-FDA approved bimatoprost 0.01% ophthalmic solution (Lumigan; Allergan) for the first-line treatment of elevated IOP in patients with open-angle glaucoma or OHT with a view to expanding the medical treatment options for glaucoma. Bimatoprost 0.01% has a similar overall safety profile, a favorable hyperemia profile, and less overall discontinuation compared with bimatoprost 0.03%. Although the new formulation of bimatoprost has a lower concentration of the active drug, it also has a higher concentration of benzalkonium chloride (BAK), 0.02% versus 0.005% in the original formulation. The BAK concentration in bimatoprost 0.01% is now the same as the BAK concentration found in latanoprost ophthalmic solution.
In lieu of its poor efficacy, unoprostone has lost its hold in the antiglaucoma palate. In fact, at the 117th Annual Meeting of the Japanese Ophthalmological Society held in Tokyo, 4–5th April 2013, the results of a Phase-II clinical trial involving the use of unoprostone in retinitis pigmentosa were announced. The trial suggested that high dose (two drops topically twice in the morning and evening) administration of topical unoprostone causes long-term maintenance of salvageable visual function and improved central retinal sensitivity. The European Medicines Agency (EMA) in the European Union and US-FDA (United states Food and Drug Administration) have now granted Sucampo Pharmaceuticals orphan drug designation in manufacturing unoprostone for the treatment of retinitis pigmentosa.,
Travatan Z (travoprost) is a new formulation of Travatan solution in which BAK is replaced with SofZia, a robust ionic-buffered preservative system that is gentle to the ocular surface. Travatan Z was approved by the US-FDA for ophthalmic topical use in glaucoma on September 21, 2006. Second, travoprost 0.004% caused not only a higher percentage of hyperemia but also a higher percentage of eyelash changes than timolol, latanoprost, or travoprost 0.0015%. As a result, travoprost 0.004% has now been discontinued from the market. However, the US-FDA later made a determination that travoprost was not discontinued for reasons of safety or effectiveness which was published in its journal dated November 16, 2011.
| Conclusion|| |
The wide variety of topically effective antiglaucoma drugs which are available today and few others in the developmental stage represent significant advancement in ocular therapeutics. Though these topical ophthalmic preparations have reduced the risk of systemic toxicity to quite an extent, their long-term use causes ocular as well as systemic toxicity which is rarely fatal. Ophthalmologists must select the drugs individually and replace them regularly to prevent habituation phenomenon and negative side effects. A new futuristic glaucoma therapeutic management paradigm where clinical success is no longer simply measured by achieved level of IOP control but also long-term preservation of visual function and patient's quality of life is expected to dramatically improve upon current treatment algorithms for OHT and glaucoma. Moreover, tafluprost seems to be a promising new venture in the right direction. Better understanding of the underlying genetic basis of heritable forms of glaucoma should provide new diagnostic tools and potential for new therapeutic avenues. A great deal of research is being directed toward applying new molecular and cellular techniques to induce regeneration of mammalian central nervous axons. This shall be an important step in therapy for glaucomatous optic nerve atrophy (which can lead to at least partial recovery of optic nerve function following atrophy from glaucoma). The search for pharmacological and neuroregenerative agents for the treatment of glaucoma promises to be most exciting pathways for the future treatment of glaucoma.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. The AGIS Investigators. Am J Ophthalmol 2000;130:429-40.
Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, et al
. The Ocular Hypertension Treatment Study: A randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:701-13.
Rhee DJ, Migdal CS. Which therapy to use in glaucoma? In: Yanoff M, Duker J. Textbook of Ophthalmology. Ch. 10.23. Philadelphia: Elsevier – Health Sciences Division; 2009. p. 1216-9.
Svensson N. The Magic molecule that jas improved millions of lives. Available form :
Allingham RR. Prostaglandins and hypotensive lipids. In: Allingham RR, Damji KF, Freedman S, Moroi SE, Rhee DJ, editors. Shields Textbook of Glaucoma. 6th ed., Ch. 28. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2011. p. 402-11.
Gross RL. Current medical management of glaucoma. In: Yanoff M, Duker J, editors. Textbook of Ophthalmology. Ch. 10.24. Philadelphia: Elsevier – Health Sciences Division; 2009. p. 1220-6.
Woodward DF, Liang Y, Krauss AH. Prostamides (prostaglandin-ethanolamides) and their pharmacology. Br J Pharmacol 2008;153:410-9.
Chen J, Krauss AH, Gil DW, Lai RK, Protzman CE, et al
. Pharmacological characterization of AGN 192024 (Lumigan) in ocular and non-ocular preparations and its relation to the prostamides. Invest Ophthalmol Vis Sci Suppl 2001;42:S832.
Zioptan Information Sheet. Available from:
[Last accessed on 2015 Dec 29].
Zhang WY, Po AL, Dua HS, Azuara-Blanco A. Meta-analysis of randomised controlled trials comparing latanoprost with timolol in the treatment of patients with open angle glaucoma or ocular hypertension. Br J Ophthalmol 2001;85:983-90.
Fung AT, Reid SE, Jones MP, Healey PR, McCluskey PJ, Craig JC. Meta-analysis of randomised controlled trials comparing latanoprost with brimonidine in the treatment of open-angle glaucoma, ocular hypertension or normal-tension glaucoma. Br J Ophthalmol 2007;91:62-8.
Schwenn O, Heckmann B, Guzy C, Miller PJ. Long-term effect of latanoprost/timolol fixed combination in patients with glaucoma or ocular hypertension: A prospective, observational, noninterventional study. BMC Ophthalmol 2010;10:21.
Higginbotham EJ, Feldman R, Stiles M, Dubiner H; Fixed Combination Investigative Group. Latanoprost and timolol combination therapy vs monotherapy: One-year randomized trial. Arch Ophthalmol 2002;120:915-22.
Cheng JW, Xi GL, Wei RL, Cai JP, Li Y. Efficacy and tolerability of latanoprost compared to dorzolamide combined with timolol in the treatment of patients with elevated intraocular pressure: A meta-analysis of randomized, controlled trials. J Ocul Pharmacol Ther 2009;25:55-64.
Cheng JW, Wei RL. Meta-analysis of 13 randomized controlled trials comparing bimatoprost with latanoprost in patients with elevated intraocular pressure. Clin Ther 2008;30:622-32.
Brandt JD, VanDenburgh AM, Chen K, Whitcup SM; Bimatoprost Study Group. Comparison of once- or twice-daily bimatoprost with twice-daily timolol in patients with elevated IOP: A 3-month clinical trial. Ophthalmology 2001;108:1023-31.
Coleman AL, Lerner F, Bernstein P, Whitcup SM. A 3-month randomized controlled trial of bimatoprost (LUMIGAN) versus combined timolol and dorzolamide (Cosopt) in patients with glaucoma or ocular hypertension. Ophthalmology 2003;110:2362-8.
Martinez A, Sanchez M. Bimatoprost/timolol fixed combination vs latanoprost/timolol fixed combination in open-angle glaucoma patients. Eye (Lond) 2009;23:810-8.
Doi LM, Melo LA Jr., Prata JA Jr. Effects of the combination of bimatoprost and latanoprost on intraocular pressure in primary open angle glaucoma: A randomised clinical trial. Br J Ophthalmol 2005;89:547-9.
Aung T, Chew PT, Yip CC, Chan YH, See JL, Khng CG, et al
. A randomized double-masked crossover study comparing latanoprost 0.005% with unoprostone 0.12% in patients with primary open-angle glaucoma and ocular hypertension. Am J Ophthalmol 2001;131:636-42.
Stewart WC, Sharpe ED, Stewart JA, Holmes KT, Latham KE. Additive efficacy of unoprostone isopropyl 0.12% (rescula) to latanoprost 0.005%. Am J Ophthalmol 2001;131:339-44.
Inoue K, Noguchi K, Wakakura M, Tomita G. Effects of unoprostone on diurnal variation of intraocular pressure in healthy volunteers. Clin Ophthalmol 2011;5:1003-5.
Eve Higginbotham. Travatan clinical trial. Ocular Surgery News, U.S. Edition, 15, March, 2001.
Li N, Chen XM, Zhou Y, Wei ML, Yao X. Travoprost compared with other prostaglandin analogues or timolol in patients with open-angle glaucoma or ocular hypertension: Meta-analysis of randomized controlled trials. Clin Experiment Ophthalmol 2006;34:755-64.
Netland PA, Landry T, Sullivan EK, Andrew R, Silver L, Weiner A, et al
. Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol 2001;132:472-84.
Fellman RL, Sullivan EK, Ratliff M, Silver LH, Whitson JT, Turner FD, et al
. Comparison of travoprost 0.0015% and 0.004% with timolol 0.5% in patients with elevated intraocular pressure: A 6-month, masked, multicenter trial. Ophthalmology 2002;109:998-1008.
Schuman JS, Katz GJ, Lewis RA, Henry JC, Mallick S, Wells DT, et al
. Efficacy and safety of a fixed combination of travoprost 0.004%/timolol 0.5% ophthalmic solution once daily for open-angle glaucoma or ocular hypertension. Am J Ophthalmol 2005;140:242-50.
Parrish RK, Palmberg P, Sheu WP; XLT Study Group. A comparison of latanoprost, bimatoprost, and travoprost in patients with elevated intraocular pressure: A 12-week, randomized, masked-evaluator multicenter study. Am J Ophthalmol 2003;135:688-703.
Chabi A, Varma R, Tsai JC, Lupinacci R, Pigeon J, Baranak C, et al
. Randomized clinical trial of the efficacy and safety of preservative-free tafluprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol 2012;153:1187-96.
Erb C, Lanzl I, Seidova SF, Kimmich F. Preservative-free tafluprost 0.0015% in the treatment of patients with glaucoma and ocular hypertension. Adv Ther 2011;28:575-85.
Egorov E, Ropo A; Investigators. Adjunctive use of tafluprost with timolol provides additive effects for reduction of intraocular pressure in patients with glaucoma. Eur J Ophthalmol 2009;19:214-22.
Law SK. Bimatoprost in the treatment of eyelash hypotrichosis. Clin Ophthalmol 2010;4:349-58.
Jones D. Enhanced eyelashes: Prescription and over-the-counter options. Aesthetic Plast Surg 2011;35:116-21.
Federal Register of the US-FDA. The Office of the Federal Register (OFR) of the National Archives and Records Administration (NARA), and the U.S. Government Printing Office (GPO), USA. Available from:
. [Last accessed on 2015 Dec 29].
Japanese Ophthalmological Society, 117th Meet, Press Release. Available from:
. [Last accessed on 2015 Dec 29].
News Medical. Source Succampo Pharmacueticals, Inc. Available from:
. [Last accessed on 2015 Dec 29].
US-FDA Approval History. Available from:
. [Last accessed on 2015 Dec 29].
Federal Register of the US-FDA. The Office of the Federal Register (OFR) of the National Archives and Records Administration (NARA), and the U.S. Government Printing Office (GPO), USA. Available from:
. [Last accessed on 2016 Apr 01].