PMC:2792620 / 12827-39189 JSONTXT

{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/2792620","sourcedb":"PMC","sourceid":"2792620","source_url":"http://www.ncbi.nlm.nih.gov/pmc/2792620","text":"β BLOCKERS\nSince their introduction in 1979, β blockers have become first line therapy for glaucoma. These agents reduce intraocular pressure (IOP), thereby preventing damage to the optic nerve and subsequent loss of vision. Timolol, betaxolol, levobunolol, metipranolol, and carteolol are the topical beta-blockers available in the market. They have similar IOP-lowering efficacy, but differ in other pharmacological properties.\nTimolol has become the most widely used ocular hypotensive agent. The potential side effects associated with its nonselective beta-blockade have prevented its use in patients with reactive airways disease and with various cardiovascular conditions. Topically administered β blockers are generally well-tolerated. However, they undergo systemic absorption and can adversely affect cardiovascular and bronchopulmonary function in patients with existing diseases such as heart failure, sinus bradycardia, chronic obstructive airways disease or asthma.\nLocal adverse effects associated with β -blockers include stinging, burning, red eye, itching, tearing and loss of corneal sensitivity.[2627]\nTimolol [Figure 3], introduced in 1978, was the first β adrenocpetor antagonist approved for the treatment of glaucoma. It lowers IOP by decreasing aqueous humor formation. It reduces IOP by 20-35%, on an average.[2829] It is very effective during waking hours and causes less reduction in IOP in night.[30] Early trials demonstrated that it is more effective in lowering IOP, as compared to epinephrine and pilocarpine.[31]\nFigure 3 Structure of timolol Timolol is available as 0.25% and 0.5% ophthalmic solutions, to be applied twice daily, and also as once-daily gel (0.5%) forming solutions (Timoptic XE). With timolol, systemic complications occur more frequently, including a variety of cardiovascular, respiratory, central nervous system, gastrointestinal, and dermatologic reactions. Ocular side effects were also reported, including superficial punctate keratitis, ocular pain or discomfort, corneal anesthesia, and vague visual disturbances.[32] Timolol is the US-FDA's gold standard drug for glaucoma therapy, against which all new medications must be compared prior to approval.\n\nCarteolol\nCarteolol hydrochloride [Figure 4] ophthalmic solution, 1%, is a nonselective beta-adrenergic blocking agent with associated intrinsic sympathomimetic activity. It was hoped that the intrinsic sympthomimetic activity (ISA) of carteolol might protect against some of the systemic adverse effects such as reduced pulse and blood pressure, seen with other beta-adrenoreceptor antagonists. Given topically twice daily in controlled domestic clinical trials, carteolol produced a median percent reduction of IOP 22 to 25%. Carteolol 1% showed comparable ocular hypotensive effect and a safety profile, similar to those of timolol 0.5% solution, and it was better tolerated, with regard to stinging and irritation.[33]\nFigure 4 Structure of betaxolol\n\nLevobunolol\nLevonunalol acts by reducing aqueous humor formation and increasing outflow facility.[34] The onset of action with levobunalol is seen within one hour and the maximum effect is observed between two and six hours. A majority of it is metabolized into an active metabolite di-hydrolevobunolol, which is also effective at lowering IOP. It is used clinically in a concentration of 0.5 to 1%, twice or once a day.\nBetaxolol [Figure 4] is a relatively selective β-1 blocker, which in most patients is almost as effective as timolol in lowering intraocular pressure and may be partly additive with dipivefrin. It is probably safer in patients unable to tolerate non-selective β -blockers.[35]\nThe onset of action with betaxolol is within 30 minutes and the maximum effect is observed two hours after topical administration. It is available as 0.25% ophthalmic suspension, to be administered twice daily. Stinging upon instillation is a particularly frequent finding with betaxolol (up to 30% to 40% of patients). Unlike other topically applied beta-blockers, betaxolol plays an additional role in blocking N-methyl-Daspartate (NMDA) gated calcium channels.\n\nSystemic carbonic anhydrase inhibitors\nCarbonic anhydrase inhibitors are sulfonamide drugs, which act on the ciliary epithelium, on -carbonic anhydrase isoenzyme II catalyses conversion of CO2 and H2O to HCO3 and H+, a process important for the production of aqueous humor.\nAcetazolamide and methazolamide are able to reduce IOP, when taken orally, by decreasing aqueous production. Acetazolamide tablets (125 mg and 250 mg) and methazolamide tablets (25 and 50 mg) are available in the market. Acetazolamide is administered four times daily and methazolamide two or three times daily. Both medications cause several side effects, including paresthesia of fingertips and toes, fatigue, depression, kidney stones, thrombocytopenia, agranulocystosis, and aplastic anemia.[36]\n\nTopical carbonic anhydrase inhibitors\nDorzolamide [Figure 5] was the first topical carbonic anhydrase inhibitor launched in the market.\nFigure 5 Structure of dorzolamide Dorzolamide reduces IOP by decreasing aqueous production, through the inhibition of the enzyme carbonic anhydrase in the ciliary body. When β-blockers are contraindicated, dorzolamide may be used as a first-line therapy. It has excellent additivity with β blockers and pilocarpine.[37]\nDorzolamide is most commonly prescribed as an add-on therapy. It is available as a 2% ophthalmic solution applied three times daily. An IOP reduction of approximately 19-23% is observed.[38]\nA combination of latanoprost and dorzolamide showed additive effect in lowering the IOP in a trial with 30 patients of ocular hypertension or early capsular or primary open-angle glaucoma and elevated IOP.[39] A double-masked, randomized one-year study revealed that ocular hypotensive efficacy of 2.0% dorzolamide, given three times a day, is comparable with that of 0.5% betaxolol, given twice daily.[40] Systemic side effects are minimal, as compared with those of oral carbonic anhydrase inhibitors. However, there were local side effects, including corneal edema, borderline endothelial function, decreased visual acuity and allergic reactions. Local adverse events seen with dorzolamide include stinging, burning and itching.\n\nBrinzolamide\nBrinzolamide, available as 1% ophthalmic suspension, has been able to lower IOP as well as dorzolamide. Its pH of 7.4 equivalent to that of human tears makes it better tolerated than dorzolamide (pH 5.5) by most patients.[4142]\nA multicenter, double-masked, prospective, parallel-group study showed that brinzolamide 1.0% caused less ocular discomfort than dorzolamide 2.0%. The incidence of ocular discomfort (burning and stinging) on instillation of brinzolamide (twice daily, 1.8%; three times daily, 3.0%) was significantly less compared with the treatment with dorzolamide (16.4%).[43]\n\nProstaglandin analogs\nProstaglandins (PG) are known mediators of inflammation. At high doses, they can induce increased IOP. Conversely, at low doses prostaglandins have been shown to lower IOP.[44] Hypotensive lipids, named as eicosanoids, including latanoprost, travaprost and bimatoprost. Prostaglandin analogs [Figure 6] represent a novel class of topically active ocular hypotensive agents with a unique mechanism of action.\nFigure 6 Chemical structures of prostaglandin F2α and commercially available prostaglandin analogues\n\nLatanoprost\nLatanoprost, an ester prodrug analogue of a prostaglandin F2a (13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2a isopropyl ester) analogue, is a selective prostanoid FP receptor agonist. Several clinical trials have demonstrated that it can be combined with timolol, acetazolamide, epinephrine, and pilocarpine, probably due to its unique IOP-reducing mechanism.[45–50]\nLatanoprost reduces IOP by increasing the aqueous outflow from the eye, through the uveoscleral pathway.[51] How this occurs is not known, but it is thought that they bind to the receptors of the ciliary body and upregulate metalloproteinases. These enzymes remodel the extracellular matrix and make the area more permeable to aqueous humor, thereby increasing outflow.[52] A single drop of latanoprost 0.005% solution (about 1.5µg) once daily has been established as the most effective dosage regimen.[53]\nSince its introduction in 1996 in the US, latanoprost has become the most popular drug for the treatment of glaucoma around the world. Latanoprost has been compared with timolol in several multicentric clinical trials. Once-daily latanoprost was found to be more effective in lowering IOP than twice daily timolol. The mean IOP reduction was 6.7± 3.4 mmHg for latanoprost and 4.9±2.9 mmHg for timolol, after 6 months' treatment.[54–56]\nLatanoprost was found to be effective in reducing IOP during the evening as well as during the day.[57] A long-term study of five years with latanoprost has shown no loss in efficacy in treating glaucoma patients, for this study latanoprost was declared as the only PGA to have received a formal first-line usage approval from the US-FDA. In some studies, latanoprost was found to be equally significantly more effective in reducing IOP than dorzolamide and brimonidine.[58] In a comparative study between three PGAs latanoprost, bimatoprost, and travaprost, it was found that all the three drugs were comparable in their ability to reduce IOP in OAG and OH patients. Latanoprost exhibited greater ocular tolerability.[59] Latanoprost is available in 0.005% solution, administered in the evening and requiring refrigeration for long-term storage as well as protection from sunlight and stability.[60]\nConjunctival hyperemia occurs within the first two days after instillation of latanoprost treatment, which diminishes with time (after two to four weeks). Increased iris pigmentation has been reported in 5 to 25% of glaucoma patients treated with latanoprost. Irideal darkening may be a result of a prostaglandin-stimulated increase in melanin production.[61] Several effects on eyelid and lashes were seen, following treatment with latanoprost, including an increase in the length, number, colour and thickness.[62]\nPrevious surgery or a history of intraocular inflammation may predispose some glaucoma patients treated with latanoprost to cystoid macular oedema or uveitis. Systemic adverse effects are relatively not seen because the drug and its metabolites have rapid elimination half-life.\n[Figure 6]: Chemical structures of prostaglandin F2a and commercially available drugs belonging to prostaglandin analogues\n\nUnoprostone\nUnoprostone Isopropylate is a docosanoid, a structural analogue of an inactive biosynthetic cyclic derivative of arachidonic acid, 13, 14-dihydro-15-keto-prostaglandin F2a. Its chemical name is isopropyl (+)-(Z)-7-[(1R, 2R, 3R, 5S)-3,5-dihydroxy-2-(3oxodecyl) cyclopentyl] -5-heptenoate. It differs structurally from other PGAs in that it has a 22-carbon chain backbone, instead of the typical truncated 20-carbon structure found in other agents [Figure 1] It is available in 0.15% ophthalmic formulation, to be applied twice daily.\nUnoprostone decreases IOP by increasing the outflow facility without affecting aqueous humor production.[63] When used in monotherapy, Unoprostone provided a clinically significant IOP-lowering effect, equivalent to that of betaxolol but not to those of timolol and latanoprost.[6465] However, in another study, an aqueous solution of 0.12% unoprostone isopropyl, applied topically to the eye twice daily for six weeks, was as effective as 0.5% timolol in maintaining control of IOP in subjects with chronic open angle glaucoma or ocular hypertension.[66] In a six-month study, it was found that unoprostone isopropyl beneficially provides additive IOP lowering effect to topical β-blocker in patients with primary open angle glaucoma. No serious systemic side effects were found in the present study.[67]\nA study involving thirty healthy volunteers, Unoprostone significantly increased microcirculation in the optic nerve head (ONH) in control subjects and in normal tension glaucoma patients, without reducing the IOP significantly.[68] A long term comparative study between topical antiglaucoma therapy of timolol and unoprostone as against betaxolol and unoprostone revealed that both combined treatments were effective for IOP reduction in glaucoma patients, and the data from the Betaxolol and Unoprostone treatment group suggested that Betaxolol and Unoprostone was more effective in maintaining visual field than timolol and unoprostone.[69] Unoprostone instillation increases blood flow in the choroidretina in human eyes.[70] Iris hyperpigmentation and abnormal eyelash changes may occur after treatment with unoprostone, but the incidence of these events were low in the two-year clinical study.[71]\n\nBimatoprost\nBimatoprost ophthalmic solution 0.03% is a synthetic prostamide analog with ocular hypotensive activity. Its chemical name is (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2[1E,3S) -3-hydroxy-5-phenyl-1-pentenyl]cyclopentyl]- 5-N-ethylheptenamide.\nBimatoprost is known as prostamide analog, because of the unique structural presence of an amide ester group at the carboxy terminal end of the a carbon chain [Figure 6].\nBimatoprost interacts with a prostamide receptor in the trabecular meshwork, to increase outflow facility.[72] Bimatoprost enhances the pressure-sensitive outflow pathway and may also cause an increase in the rate of flow via the pressure-insensitive outflow pathway and a lowering of the extraocular recipient pressure.[73]\nIn a six-month multicentric, randomized controlled trial, bimatoprost proved to be statistically and clinically superior to timolol in lowering IOP in patients with glaucoma or ocular hypertension. The most frequent side effect was trace-to-mild conjunctival hyperemia. Changes in iris pigmentation were reported in 1.1% of bimatoprost patients.[74]\nA multicenter, randomized, investigator-masked, parallel-group trial bimatoprost provided lower mean pressures than latanoprost at every time point throughout the study and was statistically superior in achieving low target pressures.[75] A six-month trial study revealed that the IOP-lowering efficacies of bimatoprost and timolol-dorzolamide combination were similar; thus, bimatoprost can be used as a long-term monotherapy agent in the treatment of POAG and ocular hypertension.[76]\nBimatoprost is available in 0.03% ophthalmic solution and is administered once daily in the evening. It does not require refrigeration to maintain stability.[77]\n\nTravaprost\nTravaprost is a synthetic prostaglandin F 2a analogue. Its chemical name is isopropyl (Z)-7- [(1 R,2 R,3 R,5 S)-3,5-dihydroxy-2-[(1 E,3 R)-3-hydroxy-4-[(a,a,a-trifluoro- m -tolyl)oxy]-1- butenyl]cyclopentyl]-5-heptenoate. Following absorption into the eye, the free acid form of travaprost interacts with the endogenous FP prostanoid receptor, to enhance aqueous humor outflow and lower intraocular pressure (IOP). It differs from other PGAs, which exhibit partial agonist activity, in that it is a full agonist at the PGF2a receptor.[78]\nIn clinical studies, travaprost once daily produced reductions in IOP of between 7-8 mmHg, from a mean baseline IOP of 25-27 mmHg, an effect similar to that noted in the case of bimatoprost or latanoprost.[79] In controlled clinical trials, travaprost 0.004% once daily, used as monotherapy, produced greater IOP reduction than timolol 0.5% b.i.d and equal or greater reduction than latanoprost 0.005%.[80]\nTravaprost 0.004% was also shown to be an effective adjunctive agent, offering an additional 5 - 7 mmHg IOP reduction in patients inadequately controlled on timolol 0.5%. In trial, it was observed that travaprost monotherapy had better lowering than dorzolamide 2.0% timolol maleate 0.5% fixed combination.[81]\nTravaprost provides robust lowering of IOP with little diurnal fluctuation and results in low target pressures in a large percentage of the patients.[82] It is very stable compound, to be applied once daily in the evening. It does not require refrigeration and protection from sunlight.[83]\nMacular oedema, including cystoid macular oedema, is cited as a warning in the US product labeling for travaprost, as it is for other prostaglandin analogues.\n\nCombination therapy\nWhen a single therapy is not sufficient to lower the IOP, a combined treatment is indicated. The combination therapy is also dependent upon the mechanism through which the components act to reduce IOP. When choosing an agent for combination therapy, it should be borne in mind that those drugs with complementary mechanisms of action usually work together. Fixed-combination products have the combined efficacy of two ocular hypotensive drugs and the convenience of a two-drug treatment regimen in a single container, which may aid patient adherence to treatment. If a beta-blocking agent is used as an initial treatment, adding a topical CAI can provide an additional reduction in IOP.[84] Another combination product comprises 0.005% latanoprost and 0.5% timolol. The addition of latanoprost to timolol treatment produces an additional IOP reduction of 13-37%, depending upon the frequency of the application and the baseline IOP. Available fixed-combination products consist of timolol 0.5% as an invariant, with brimonidine 0.2%, dorzolamide 2%, travaprost 0.004%, latanoprost 0.005% or bimatoprost 0.03%.[85]\nThe range of reported additional reductions in IOP, compared to a latanoprost monotherapy baseline are as follows: latanoprost-timolol (13-37%), latanoprostpilocarpine 2% (7-14%), latanoprost and carbonic anhydrase inhibitors (15-24.1%), and latanoprost and dipivefrin (15-28%).[86]\nBrimonidine 0.2% combined with 0.5% timolol is the newest fixed combination product in the market. Clinical trials have demonstrated that dorzolamide/timolol (1 drop per eye twice daily) is an effective and generally well-tolerated fixed combination for lowering IOP in patients with open angle glaucoma or OH, including individuals uncontrolled on β -adrenoceptor antagonist monotherapy.[87]\n\nLaser procedures\nA secondary choice of treatment of glaucoma is the use of laser therapy. The primary strategy involves ‘burning’ holes in various areas within the eyes, including the ciliary and the pigmented trabecular meshwork cells.[88]\nArgon laser trabeculoplasty (ALT) targets trabecular meshwork, where it allows the aqueous fluid to leave the eye more efficiently. The procedure requires 10-20 minutes and 80% of the patients respond well to it and may eventually discontinue glaucoma medications.[89]\nThe Nd : YAG (neodymium-doped yttrium aluminium garnet) laser can also be used in closed-angle glaucoma to make a small peripheral hole in the iris, to allow the aqueous fluid to flow easily. Selective laser trabeculoplasty (SLT) delivers energy to pigmented trabecular meshwork cells in a process called photo-thermolysis. The advantage of SLT is that nonpigmented trabecular meshwork (TM) cells may sustain less damage compared with ALT.[90]\n\nSurgery\nTrabeculectomy should be considered in all patients, when the ‘target IOP’ is not achieved with glaucoma medications and if the expected rate of visual loss could affect the patient during their lifetime. In this procedure, an opening is made in the trabecular meshwork, so that aqueous humor can drain into the sclera.\nMany patients can discontinue glaucoma medications after surgery. Approximately one-third of the trabeculectomy patients develop cataract within five years. If trabeculectomy fails, another type of surgery places a drainage tube (Molteno tube) in the eye, between the cornea and iris, which exits at the junction of the cornea and sclera. Cyclodestructive procedures, which lower IOP by destroying the ciliary body, are typically reserved for eyes, which are refractory to all other forms of therapy. These procedures include cyclocryotherapy, cylcodiathermy and laser cyclophotocoagulation.[91–93]\n\nComplementary and alternative system of medicine\nIn recent times, there has been an increased interest in complementary medicine. But very little research has been done on the majority of herbal remedies, with regard to their effect on glaucoma. There are several nutrients and botanicals that hold promise for the treatment of glaucoma, but most studies are preliminary, and larger, controlled studies are required.[94]\nForskolin is a diterpine derivative of the plant Coleus forskohlii, which acts on adenylate cyclase catalytic subunit to increase intracellular cAMP. Gingko biloba extract has multiple beneficial actions, which will be helpful in the treatment of glaucoma, like increased ocular blood flow, antioxidant activity, platelet activating factor inhibitory activity, nitric oxide inhibition, and neuroprotective activity combine, suggesting that Gingko biloba extract could be used in the treatment of glaucoma.[95]\nIn a recent trial in Italy, which was a randomized, placebo-controlled, double masked trial involving 27 patients, there was an improvement in the visual fields in-patient, with normal tension glaucoma after four weeks of treatment with Ginkgo biloba.[96]\nAlpha lipoic acid, a powerful antioxidant, may be useful in glaucoma, because it reduces nerve cell damage from oxidative stress.[97] Supplementation with Vitamin C is believed to increase aqueous humor drainage, through reducing the viscosity of hyaluronic acid in the trabecular meshwork.\nIn China, the main herb-derived eye drops for glaucoma are pueraria flavonoids, areca seed extract, and alkaloids from erycibe (Erycibe obtusifolia; dinggongteng aka baogongteng). These eye drops appear to work as well or better than pilocarpine, which is usually used as a comparative standard.[98] Salvia miltiorrhiza is a Chinese herb, injected intravenously (solution) and which helps to improve microcirculation of the retinal ganglion cells.\nCannabinoids reduce intraocular pressure by enhancing uveoscleral outflow. The development of formulation for ocular administration has not yet yielded a prescription medication.\n\nFuture glaucoma therapy\nA number of potential strategies for the development of a novel therapy for glaucoma are: glutamate inhibition, NMDA receptor blockade, exogenously applied neurotrophins, open channel blockers, antioxidants, protease inhibitors and gene therapy.\n\nNMDA receptor antagonists\nNMDA antagonist provides neuroprotection by blocking pathological increase in glutamate, which drives cell death by facilitating calcium entry into a cell. Memantine, an N-methyl-D-aspartate subtype glutamate receptor antagonist is in the clinical stage of development, and, if there is proof of efficacy of memantine, it will change the treatment paradigm for glaucoma.[99]\nIn addition to memantine, a number of other potential non-IOP lowering direct acting neuroprotective agents are shown to have an application in glaucoma. Many of these agents focus on other routes of overcoming glutamate cytotoxicity.\nCompounds on clinical trials are –\nEliprodil: It is a non-competitive NMDA antagonist; providing protection from glutamate mediated cytotoxicity to retinal ganglion cells.\nRiluzole: It is a presynaptic glutamate release inhibitor, which has shown to have potential neuroprotective utility.\nL-deprenyl: An inhibit apoptosis of serum deprived retrovirus-immortilised retinal ganglion cells in vivo, it can decrease the apoptosis index of primary mix retinal cells, when deprived of specific neurotropic factors.\n\nNeuroprotective vaccines\nSince resistance to high IOP is immune-dependent, T-cell induced neuroprotection may vaccinate the RGC from apoptosis. An example of a neuroprotective vaccine is R16, a peptide (interphotoreceptor-retinoid binding protein) derived from the RGC.[100]\n\nSTAT-3 activation\nSignal transducers and activators of transcription protein-3 (STAT-3) play an important role in cell growth and differentiation. They are considered important because the mRNA of this protein is upregulated in rats with glaucoma. Ciliary neurotrophic factor (CNTF), which is an interleukin-6 cytokine injected into the eyes of rats with increased IOP reduced apoptosis, phosphorylated STAT-3, and reduced the activity of caspase-3. Interleukin-10 also has neuroprotective activity, which promotes survival of RGCs, due to IL-10 signaling through the STAT-3 pathway.[101–103]\n\nErythropoietin\nErythropoietin is a hematopoietic cytokine, which has been shown to possess remarkable tissue-protective and neuroprotective properties that may prevent further RGC death by inhibiting apoptosis.[104] Intravitreal injection of Erythropoietin in rats with axotomized RGCs enhances RGC survival by 92%, as compared to those without EPO injection.[105] In addition, EPO reduces caspase activity, indicated by a decrease in the absorbance of colorimetric caspase substrates. However, further studies are needed to fully evaluate the safety and efficacy of this neuroprotective agent in clinical trials.[106]\n\nCaspase inhibitors\nGene therapy represents an attractive approach for the treatment of eye diseases such as glaucoma. Inhibitors of apoptosis protein (IAP) can also reduce apoptosis by inhibiting caspase. Ocular administration of viral vectors produces localized retinal gene expression with reduced risks of side effects reported with systemic administration of viral vectors. Rats were given unilateral intravitreal injections of AAV-CBA vector coding for human baculoviral IAP repeat-containing protein-4 (BIRC4), a potent caspase inhibitor. Gene therapy delivering BIRC4 significantly promoted optic nerve axon survival in a chronic ocular hypertensive model of rat glaucoma. Blocking RGC apoptosis with caspase inhibitors represents a promising approach for treatment of human glaucoma.[107108]\n\niNOS-2 Inhibitors\nSince the upregulation of iNOS-2 is harmful to neurons, its inhibition might have a neuroprotective effect. Although an unregulated level of NO can cause neuronal degeneration via apoptosis, a small amount of NO could inhibit apoptosis. Survival of serum deprived pheochromocytoma PC-12 cells was observed when treated with an NO donor. These results indicate that the cytoprotective effect of nipradilol in PC12 cell death was due to the caspase-3 inhibition mediated by NO-related S-nitrosylation and activation of protein kinase G.[109]\n","divisions":[{"label":"Title","span":{"begin":0,"end":10}},{"label":"Figure caption","span":{"begin":1546,"end":1578}},{"label":"Section","span":{"begin":2216,"end":2974}},{"label":"Title","span":{"begin":2216,"end":2225}},{"label":"Figure caption","span":{"begin":2939,"end":2973}},{"label":"Section","span":{"begin":2973,"end":4134}},{"label":"Title","span":{"begin":2973,"end":2984}},{"label":"Section","span":{"begin":4136,"end":4909}},{"label":"Title","span":{"begin":4136,"end":4174}},{"label":"Section","span":{"begin":4911,"end":6292}},{"label":"Title","span":{"begin":4911,"end":4948}},{"label":"Figure 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