Topical medication instillation techniques for glaucoma

  • Protocol
  • Intervention

Authors


Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To investigate the effectiveness of topical medication instillation techniques in the management of glaucoma, including primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), and secondary glaucomas.

Background

Description of the condition

Definition of glaucoma

Glaucoma is a progressive optic neuropathy. If left undiagnosed and untreated, the optic nerve of patients with glaucoma may sustain irreversible damage (Lee 2005). At the end stage, patients suffer from permanent visual field loss and blindness (Marquis 2005).

Factors associated with increased risk for the development of glaucoma include elevated intraocular pressure (IOP), increasing age, a positive family history of glaucoma, African or Asian racial background, near-sightedness, and thinner central corneal thickness (Alsbirk 1976; Armaly 1980; Coleman 2008; Ernest 2013; Landers 2002; Le 2003; Medeiros 2003; Tielsch 1996). Elevated IOP is viewed as a major risk factor of glaucoma rather than a defining feature of the condition because elevated IOP and glaucomatous optic neuropathy (GON) do not necessarily coexist (Casson 2012). Additionally, IOP is the only known risk factor that can be modified.

Epidemiology of glaucoma

Glaucoma is a significant public health problem in that it is the leading cause of irreversible blindness worldwide and the second most common cause of blindness after cataracts (Heijl 2009; Pan 2011; Quigley 1996). In 2006, Quigley (Quigley 2006) projected that 60.5 million and 79.6 million people would be diagnosed with glaucoma worldwide in 2010 and in 2020, respectively. These numbers would represent 2.65% and 2.86% of the global population over 40 years of age, respectively, in 2010 and 2020. The number of people bilaterally blind from primary glaucoma was estimated to be more than 8.4 million in 2010, rising to 11.2 million by 2020. In the United States, 10% of people who are bilaterally blind are believed to be blind secondary to glaucoma (Congdon 2004). Primary open-angle glaucoma (POAG) is the most common type of glaucoma, accounting for 74% of all persons with glaucoma (Quigley 1996).

Glaucoma treatment

Because no treatment has been proven to repair or regenerate a damaged optic nerve, the primary purpose of glaucoma therapy is to manage IOP to a target level at which progressive glaucomatous optic neuropathy and vision loss are stopped or delayed (Lee 2005). IOP reduction is the only current evidence-based treatment strategy for all types of glaucoma, including normal tension glaucoma (NTG) (Casson 2012). In general, three main treatments for glaucoma are directed toward reducing IOP: medical therapy, laser therapy, and incisional surgery. Although each of these types of treatments is effective in lowering IOP to some extent, therapy usually begins with medications. To reduce IOP further to a target level, medications can be used as supplemental treatment with laser or surgery when laser or surgery alone is not successful in reaching the target postoperative IOP.

The mechanics of medications in lowering IOP involve reducing aqueous humor production or increasing the rate of outflow of aqueous humor within the eye. For most patients, one or more topical medications are effective in reducing IOP. Many medical treatments, usually applied topically, are available for this purpose (e.g., prostaglandin analogs, beta-blockers, alpha2-selective adrenergic agonists, cholinergic agonists, carbonic anhydrase inhibitors) (Noecker 2006).

Description of the intervention

Many topical antiglaucoma medications are associated with systemic side effects. For example, beta-blockers have been associated with arrhythmias, congestive cardiac failure, and airway obstruction (Ehongo 2007); and carbonic anhydrase inhibitors may cause thrombocytopenia (Beckers 2008; Cantor 1989). To increase the therapeutic index (Zimmerman 1984) of antiglaucoma medications (i.e., to increase the desired therapeutic effect while reducing the undesired side effects), various techniques for applying medications topically have been suggested. Examples of topical medication instillation techniques include eyelid closure (ELC), nasolacrimal (tear drainage) occlusion (NLO), changes in the proximity of the eye-dropper tip to the eyes (contact vs no contact), instillation of drops into the conjunctival sac, removal of excess fluid after instillation, and delayed time interval between instillation of multiple topical medications. These techniques are designed to improve ocular bioavailability and to lower systemic absorption of the drug during instillation of topical medications to achieve the goal of increasing the therapeutic index (Bourlais 1998; Shell 1984; Zimmerman 1983). ELC involves gently closing the eyes for several minutes after the medication is applied, to prolong eye-drug contact and to block drainage of the drug into the nasopharyngeal mucosa. NLO is achieved by applying pressure over the area between the bridge of the nose and the inner canthus, known as the periphery of the nasolacrimal drainage system, to block tear drainage.

How the intervention might work

When ocular medications are instilled topically, some medication may spill out of the eye or may not be completely absorbed by the target area. Some studies have suggested that as much as 90% of topical eye drops is wasted or is not absorbed intraocularly (Chang 1988; Gupta 2012; Lee 1986). When drug absorption into the eye is limited, most of the medication is absorbed into the nasopharyngeal mucosa through the nasolacrimal duct. With increased contact time between topically applied medicine and the ocular surface, and with obstruction of drainage of the medicine into the nasopharyngeal mucosa, intraocular medicine concentrations may be increased. When more of the medicine remains available locally, a greater number of medicine molecules may reach the intended intraocular receptors, increasing the desired ocular effects, and fewer medicine molecules may reach the circulatory system, decreasing undesired side effects through systemic absorption. Numerous reports have described cardiovascular and respiratory complications associated with timolol, a widely used nonselective beta-antagonist antiglaucoma medication, since its introduction in 1978 (Katz 1983; Levine 1982; Zimmerman 1981). Topical medication instillation techniques have been shown not only to reduce systemic timolol absorption (Kaila 1986; Passo 1984; Zimmerman 1984) but also to enhance ocular penetration of the medicine (Ellis 1992; Fraunfelder 1976; Zimmerman 1984).

Why it is important to do this review

Various topical medication instillation techniques have been recommended for administering ocular treatments. Some studies suggest that NLO or ELC may enhance intraocular absorption (Ellis 1992; Fraunfelder 1976; Zimmerman 1984) and/or reduce systemic absorption (Kaila 1986; Passo 1984; Zimmerman 1984) of topically applied glaucoma medications. On the other hand, it is not clear whether reducing systemic absorption or enhancing intraocular absorption leads to an increased therapeutic effect of medication (Sleath 2011). Because of these controversies, it is necessary to systematically review and summarize data regarding instillation techniques for their effectiveness, feasibility, and practicality. However, to date no such review has been published (Li 2012).

Objectives

To investigate the effectiveness of topical medication instillation techniques in the management of glaucoma, including primary open-angle glaucoma (POAG), primary angle-closure glaucoma (PACG), and secondary glaucomas.

Methods

Criteria for considering studies for this review

Types of studies

We will include randomized controlled trials (RCTs) in this review.

Types of participants

We will include RCTs of participants prescribed topical eye medication for the treatment or control of POAG, PACG, or secondary glaucoma (such as pigmentary glaucoma or capsular glaucoma). We also will include studies that included participants suspected to have ocular hypertension or glaucoma.

Types of interventions

We will include RCTs comparing patient education about topical medication instillation techniques with no patient education, usual care, or a different method of instillation of topical medication. Topical medication instillation techniques may include eyelid closure, nasolacrimal occlusion, making sure the dropper does not touch the ocular area, instillation of drops into the conjunctival sac, removal of excess fluid after instillation, and delayed time interval between instillation of multiple topical medications.

Types of outcome measures

Primary outcomes

The primary outcome of the review will be the reduction of IOP from baseline measured as the:

  • Proportion of participants with IOP < 21 mm Hg at one year.

  • Mean IOP change from baseline at one year.

Secondary outcomes

Secondary outcomes will include, whenever available, (1) patient-reported outcomes related to the ease, convenience, and comfort of instillation techniques, (2) physiologic measurements of systemic absorption, and (3) escalation of therapy (such as added medications, laser trabeculoplasty, and/or surgery).

Other secondary outcomes will include mean change in IOP, mean change in visual fields, optic nerve progression (measured by mean change in cup/disc ratio), mean change in best-corrected visual acuity, and development of glaucoma at three months, six months, one year, and subsequent years of follow-up. We also will report ocular and systemic adverse events, quality of life outcomes, and cost-effectiveness outcomes when available. Specific ocular and systemic adverse events for various glaucoma drug classes are shown in Table 1.

Table 1. Commonly reported adverse effects of medical glaucoma treatments
Drug classOcular side effectsSystemic side effects
Alpha-agonists (e.g., apraclonidine, brimonidine)

Allergic reactions

Blurred vision

Burning/stinging/discomfort

Follicular conjunctival response

Hyperemia

Itching

Photophobia

Allergic reactions

Drowsiness

Dry mouth

Fatigue

Headache

Hypotension

Beta-blockers (e.g., betaxolol, carteolol, levobunolol, timolol)

Allergy

Blurred vision

Burning/stinging/discomfort

Corneal erosion

Dry eyes

Hyperemia

Hypotony

Ptosis

Superficial punctate keratitis

Visual disturbances

Bradycardia

Depression

Dizziness or light-headedness

Fatigue

Headache

Indigestion or heart pain

Insomnia

Joint pain

Nausea

Shortness of breath

Carbonic anhydrase inhibitors (e.g., acetazolamide, brinzolamide, dorzolamide)

Allergy

Blurred vision

Burning/stinging/discomfort

Dry eyes

Foreign body sensation

Hyperemia

Photophobia

Superficial punctate keratitis

Allergic reactions

Bitter or metallic taste

Dizziness

Fatigue

Gastrointestinal distress

Headache

Parasympathomimetics (e.g., carbachol, pilocarpine)

Blurred vision

Burning/stinging/discomfort

Eyelid twitching

Hyperemia

Itching

Increased tearing

Poor vision in dim light

Visual disturbances

Dizziness

Headache

Hypoglycemia

Increased saliva

Increased sweating

Nausea

Prostaglandin analogues (e.g., bimatoprost, latanoprost, travoprost)

Blurred vision

Burning/stinging/discomfort

Dry eyes

Eyelash growth

Foreign body sensation

Hyperemia

Increased tearing

Iris discoloration

Itching

Photophobia

Cold symptoms

Exacerbation of asthma

Facial rash

Joint or muscle pain

Upper respiratory infection

Search methods for identification of studies

Electronic searches

We will search the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, EMBASE, Latin American and Caribbean Health Sciences Literature Database (LILACS), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We will not use any date or language restrictions in the electronic searches for trials.

See: Appendices for details of search strategies for CENTRAL (Appendix 1), MEDLINE (Appendix 2), EMBASE (Appendix 3), LILACS (Appendix 4), mRCT (Appendix 5), ClinicalTrials.gov (Appendix 6) and the ICTRP (Appendix 7).

Searching other resources

We will search the reference lists of included studies for additional studies not identified by the electronic searches. We will use the Science Citation Index (Web of Science) to search for additional studies that may have cited included studies. We will not handsearch journals or conference abstracts specifically for the purpose of this review.

Data collection and analysis

Selection of studies

Two review authors (LX and MW) independently will assess titles and abstracts identified through the searches and will classify each record as (1) relevant or potentially relevant, (2) unclear, or (3) definitely not relevant to this review. We will obtain the full text article for records classified as (1) or (2), and two review authors (LX and MW) will independently assess each for inclusion or exclusion. We will document studies excluded after review of the full text publication, as well as provide reasons for excluding. When a study’s eligibility is unclear after full text review, we will attempt to contact the authors of the publication for clarification. If no response or clarification is received within six weeks, we will reassess the study on the basis of available information or will list it as “awaiting assessment.” Discrepancies at any stage of assessment will be resolved by discussion.

Data extraction and management

Two review authors (LX and XW) will independently extract data related to study characteristics, methodologic quality, and outcomes using data forms developed by the Cochrane Eyes and Vision Group for the purposes of this review. One review author will enter the data into Review Manager 5.2, and a second review author will verify the data entered. We will resolve discrepancies by discussion. We will attempt to contact study investigators to obtain missing data. If no response or clarification is received within six weeks, we will use the data available or will report the study results as unclear.

Assessment of risk of bias in included studies

Two review authors will independently assess the sources of systematic bias in included studies according to the methods described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011a). We will consider the following parameters when assessing risk of bias:

  • Selection bias (random sequence generation and allocation concealment).

  • Performance bias (masking of study personnel).

  • Detection bias (masking of outcome assessors).

  • Attrition bias (completeness of follow-up and intention-to-treat (ITT) analysis).

  • Reporting bias.

  • Other potential sources of bias (such as funding source).

Masking of study participants will not be assessed because of differences in the interventions under investigation.

We will assess each risk of bias parameter as having a "low risk of bias," a "high risk of bias," or an "unclear risk of bias" (insufficient information to permit judgment of low or high risk). We will attempt to contact study investigators whenever the methods are unclear or when additional information is needed to make an assessment. If no response or clarification is received within six weeks, we will classify the study on the basis of available information. Disagreements between review authors will be resolved through discussion.

Measures of treatment effect

One primary outcome for this review-the proportion of participants with IOP <21 mm Hg at one year-is a dichotomous outcome, and the measure of effect will be reported as a risk ratio with 95% confidence intervals. The mean change in IOP is a continuous outcome, and the measure of effect will be reported as a mean difference between groups with 95% confidence intervals. Patient-reported outcomes related to the ease, convenience, and comfort of instillation techniques may vary substantially and thus will be assessed as reported by included studies. We will assess continuous secondary outcomes, including mean changes in IOP, mean changes in visual fields, optic nerve progression, and mean changes in best-corrected visual acuity, as mean differences between groups with 95% confidence intervals. We will report the secondary outcome of development of glaucoma as a risk ratio with 95% confidence intervals. If continuous data are reported for quality of life outcomes or economic outcomes, the measure of effect will be reported as mean differences between groups with 95% confidence intervals.

Unit of analysis issues

The unit of analysis will be the individual when possible. If studies included both eyes of participants, we will refer to Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b) for unit of analysis issues. We will consider the unit of analysis to be the individual for studies in which both eyes of participants were included and the analysis was performed using (1) the average of both eyes, (2) the "worse" eye only, (3) one eye randomly selected for each participant, or (4) right eyes and left eyes as separate groups. We will consider studies that randomly assigned individuals to treatment groups but analyzed eyes separately as cluster randomized trials. These studies will be documented, and we will conduct sensitivity analyses to determine their impact on summary results when applicable. We will include intra-comparative studies in which one eye of a participant was assigned to one treatment group and the fellow eye was assigned to another treatment group and will document whether paired analysis was performed by study investigators to account for the correlation between the two eyes of a person.

Dealing with missing data

We will contact study investigators to ask for additional information when data are missing or incomplete. We will set the response time at six weeks; if no reply is received in that time, we will use the data available.

Assessment of heterogeneity

We will use the I2 test to examine heterogeneity. An I2 value greater than 60% will be interpreted as indicating substantial statistical heterogeneity. If substantial statistical heterogeneity is present, we will not conduct a meta-analysis and will instead report the study results independently. Clinical heterogeneity will be assessed on the basis of characteristics of participants in included studies, including glaucoma status and length of time with glaucoma, age, race, and underlying comorbidities (such as arthritis). We will also assess heterogeneity among instillation methods, such as which type of method was used, how many medications were used, and whether medications were self-administered or administered by a caregiver.

Assessment of reporting biases

We will assess selective outcome reporting bias at the individual study level. We will compare variables that were measured during the study and outcomes that were specified a priori when study protocols are available with reported study results to assess studies as having high, low, or unclear risks of selective outcome reporting bias. If data from at least 10 studies are included in a meta-analysis, we will examine the symmetry of funnel plots to assess publication biases.

Data synthesis

If no substantial statistical or clinical heterogeneity is identified, we will combine results in a meta-analysis. We will use a fixed-effect model for meta-analyses that include fewer than three studies and a random-effects model for meta-analyses consisting of three or more studies. We will calculate the summary mean difference with 95% confidence intervals for continuous outcomes and the summary relative risk with 95% confidence intervals for dichotomous outcomes. For study results that are not adequate for meta-analysis, we will summarize the overall treatment effects for each outcome as reported by each study.

Subgroup analysis and investigation of heterogeneity

When sufficient data are available, we will conduct subgroup analyses based on age (65 years and older), gender, race, type and number of medications, dose of medications, baseline glaucoma status (e.g., POAG, PACG, secondary glaucoma, glaucoma suspect, ocular hypertension), and whether medications were instilled by the patient (self-administered) or by a caregiver.

Sensitivity analysis

When sufficient data are available, we will conduct sensitivity analyses to assess the impact of studies with high risk of bias, unpublished studies, and industry-funded studies. We also will conduct sensitivity analyses for studies in which the unit of analysis was the eyes rather than the individual.

Acknowledgements

We acknowledge the Cochrane Eyes and Vision Group (CEVG) for assisting with the preparation of this protocol. We thank Lori Rosman, Trial Search Co-ordinator for CEVG@US, for developing the electronic search strategy. We thank the peer reviewers and editors for comments to the draft of this protocol.

Richard Wormald (Co-ordinating Editor for CEVG) acknowledges financial support for his CEVG research sessions from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health.

Appendices

Appendix 1. Appendix 1. CENTRAL search strategy

#1 MeSH descriptor: [Glaucoma] explode all trees
#2 MeSH descriptor: [Ocular Hypertension] explode all trees
#3 MeSH descriptor: [Intraocular Pressure] explode all trees
#4 glaucoma*:ti,ab,kw
#5 ((intra?ocular or ocular*) near/3 (hypertension* or tension* or pressure*)):ti,ab,kw
#6 IOP:ti,ab,kw
#7 #1 or #2 or #3 or #4 or #5 or #6
#8 MeSH descriptor: [Administration, Ophthalmic] explode all trees
#9 (ophthalm* near/3 (instill* or administ*)):ti,ab,kw
#10 MeSH descriptor: [Ophthalmic Solutions] this term only
#11 (eye drop* or eyedrop*):ti,ab,kw
#12 (((clos* or occlus* or occlud*) near/3 (eyelid* or duct* or lid*)) or ELC):ti,ab,kw
#13 (((nasolacrimal* or tear duct*) near/3 (occlus* or obstruct* or occlud*)) or NLO):ti,ab,kw
#14 #8 or #9 or #10 or #11 or #12 or #13
#15 MeSH descriptor: [Administration, Topical] this term only
#16 MeSH descriptor: [Instillation, Drug] explode all trees
#17 (topical* or drops*):ti,ab,kw
#18 ((drug* or medicat* or medicin*) adj3 (instill* or administ*)):ti,ab,kw
#19 (drop adj2 (instill* or administ*)):ti,ab,kw
#20 MeSH descriptor: [Prostaglandins, Synthetic] explode all trees
#21 ("Synthetic Prostaglandins" or "PG Analogs" or "Prostaglandin Analogues" or "Prostaglandin Analogs" or dimethylprostaglandin or methylprostaglandin or "prostaglandin 1"):ti,ab,kw
#22 (latanoprost* or PHXA41 or Xalatan or PhXA34 or 130209-82-4):ti,ab,kw
#23 (travoprost* or Travatan or AL-6221 or AL6221 or 157283-68-6):ti,ab,kw
#24 (bimatoprost* or latisse or Lumigan or AGN192024):ti,ab,kw
#25 MeSH descriptor: [Adrenergic beta-Antagonists] explode all trees
#26 ((Adrenergic near/1 beta* near/3 Blockers) or (Adrenergic near/1 beta* near/3 Blockaders) or beta* near/1 Adrenergic Blocking Agents or "Adrenergic beta Antagonists"):ti,ab,kw
#27 MeSH descriptor: [Timolol] explode all trees
#28 (Timolol* or Timoptic or Timoptol or Timacar or L-714465 or L714465 or MK-950 or MK950 or Optimol or Blocadren or 26839-75-8):ti,ab,kw
#29 MeSH descriptor: [Metipranolol] explode all trees
#30 (Metipranolol* or Methypranol or Trimepranol or Disorat or 22664-55-7):ti,ab,kw
#31 MeSH descriptor: [Carteolol] explode all trees
#32 (Carteolol* or OPC-1085 or OPC1085 or 51781-06-7):ti,ab,kw
#33 MeSH descriptor: [Levobunolol] explode all trees
#34 (Levobunolol* or PMS-Levobunolol or PMSLevobunolol or ratio-Levobunolol or Ultracortenol or Vistagan or W-6412A or W6412A or AKBeta or Apo-Levobunolol or ApoLevobunolol or Betagan or Bunolol or Novo-Levobunolol or NovoLevobunolol or W-7000A or W7000A or 47141-42-4):ti,ab,kw
#35 MeSH descriptor: [Betaxolol] explode all trees
#36 (Betaxolol* or Kerlone or Kerlon or Oxodal or SL-75212 or SL75212 or ALO-1401-02 or ALO140102 or Betoptic or Betoptima or 63659-18-7):ti,ab,kw
#37 MeSH descriptor: [Adrenergic alpha-Agonists] explode all trees
#38 ((adrenergic near/2 alpha* near/3 agonist*) or (alpha* near/2 adrenergic near/3 agent*) or (alpha* near/2 adrenergic receptor) or (alpha* near/2 adrenergic near/2 stimula*) or (alpha* near/2 adrenoceptor near/2 stimula*) or (alpha* near/3 agonist) or (alpha* sympathicomimetic) or (noradrenalin agonist*) or (noradrenergic agonist*) or (noradrenergic receptor stimulating agent*)):ti,ab,kw
#39 MeSH descriptor: [Adrenergic alpha-2 Receptor Agonists] explode all trees
#40 MeSH descriptor: [Cholinergic Agonists] explode all trees
#41 ((Acetylcholine near/2 Agonist*) or cholinergic or cholinomimetic or parasympathetic agent* or parasympathetic drug* or parasympathomimetic or parasympathomimetics):ti,ab,kw
#42 MeSH descriptor: [Carbonic Anhydrase Inhibitors] explode all trees
#43 ((Carbonic near/2 Anhydrase near/2 Inhibitor*) or (Carbonate near/2 Dehydratase near/2 Inhibitor*) or (Carboxyanhydrase near/1 Inhibitor*)):ti,ab,kw
#44 MeSH descriptor: [Acetazolamide] explode all trees
#45 (Acetazolam* or Ak-Zol or AkZol or Apo-Acetazolamide or ApoAcetazolamide or Diacarb or Diamox or Diuramide or Defiltran or Edemox or Glauconox or Glaupax or Huma-Zolamide or HumaZolamide or Acetadiazol or 59-66-5):ti,ab,kw
#46 (Brinzolamide* or Azopt or 138890-62-7):ti,ab,kw
#47 (Dorzolamide* or MK-507 or Trusopt or L-671152 or 130693-82-2):ti,ab,kw
#48 (isopropyl unoprostone* or "unoprostone isopropyl" or UF-021 or Rescula or Eescula or 69553-75-9):ti,ab,kw
#49 (brimonidine* or bromoxidine or ratio-Brimonidine or Alphagan or UK-14308 or UK-14304 or UK-14304-18 or AGN-190342 or 59803-98-4):ti,ab,kw
#50 #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 or #28 or #29 or #30 or #31 or #32 or #33 or #34 or #35 or #36 or #37 or #38 or #39 or #40 or #41 or #42 or #43 or #44 or #45 or #46 or #47 or #48 or #49
#51 MeSH descriptor: [Eye] explode all trees
#52 MeSH descriptor: [Eyelids] explode all trees
#53 MeSH descriptor: [Nasolacrimal Duct] explode all trees
#54 (ocular* or opthalm* or eye* or tear duct*):ti,ab,kw
#55 #51 or #52 or #53 or #54
#56 #50 and #55
#57 #7 and (#14 or #56)

Appendix 2. Appendix 2. MEDLINE (OvidSP) search strategy

1. Randomized Controlled Trial.pt.
2. Controlled Clinical Trial.pt.
3. (randomized or randomised).ab,ti.
4. placebo.ab,ti.
5. drug therapy.fs.
6. randomly.ab,ti.
7. trial.ab,ti.
8. groups.ab,ti.
9. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8
10. exp animals/ not humans.sh.
11. 9 not 10
12. exp glaucoma/
13. exp ocular hypertension/
14. exp intraocular pressure/
15. glaucoma*.tw.
16. ((intra?ocular or ocular*) adj3 (hypertension* or tension* or pressure*)).tw.
17. IOP.tw.
18. or/12-17
19. exp Administration, Ophthalmic/
20. (ophthalm* adj3 (instill* or administ* or solution*)).tw.
21. Ophthalmic Solutions/
22. (eye drop* or eyedrop*).tw.
23. (((clos* or occlus* or occlud*) adj3 (eyelid* or duct* or lid*)) or ELC).tw.
24. (((nasolacrimal* or 'tear duct') adj3 (occlus* or obstruct* or occlud*)) or NLO).tw.
25. or/19-24
26. Administration, Topical/
27. exp Instillation, Drug/
28. (topical* or drops).tw.
29. ((drug* or medicat* or medicin*) adj3 (instill* or administ*)).tw.
30. (Drop adj2 (instill* or administ*)).tw.
31. exp Prostaglandins, Synthetic/
32. (Synthetic Prostaglandins or PG Analogs or Prostaglandin Analogues or Prostaglandin Analogs or dimethylprostaglandin or methylprostaglandin or prostaglandin 1).tw.
33. latanoprost.rn.
34. (latanoprost* or PHXA41 or Xalatan or PhXA34 or 130209-82-4).tw.
35. travoprost.rn.
36. (travoprost* or Travatan or AL-6221 or AL6221 or 157283-68-6).tw.
37. bimatoprost.rn.
38. (bimatoprost* or latisse or Lumigan or AGN192024).tw.
39. exp Adrenergic beta-Antagonists/
40. ((Adrenergic adj1 beta* adj3 Blocker*) or (Adrenergic adj1 beta* adj3 Blockader*) or (beta* adj1 Adrenergic adj3 Blocking adj3 Agent*) or (Adrenergic adj1 beta* adj3 Antagonist*) or (beta* adj1 Adrenergic adj3 Blocking adj3 drug*) or (beta* adj2 antagonist*) or (beta* adj2 blocker*) or (beta* adj3 blocking adj2 agent*) or (beta adj3 blocking adj2 drug*) or Beta* antiadrenergic agent* or beta* sympathicolytic* or beta* sympatholytic*).tw.
41. exp timolol/
42. (Timolol* or Timoptic or Timoptol or Timacar or L-714,465 or L714465 or MK-950 or MK950 or Optimol or Blocadren or 26839-75-8).tw.
43. exp Metipranolol/
44. (Metipranolol* or Methypranol or Trimepranol or Disorat or 22664-55-7).tw.
45. exp Carteolol/
46. (Carteolol* or OPC-1085 or OPC1085 or 51781-06-7).tw.
47. exp Levobunolol/
48. (Levobunolol* or PMS-Levobunolol or PMSLevobunolol or ratio-Levobunolol or Ultracortenol or Vistagan or W-6412A or W6412A or AKBeta or Apo-Levobunolol or ApoLevobunolol or Betagan or Bunolol or Novo-Levobunolol or NovoLevobunolol or W-7000A or W7000A or 47141-42-4).tw.
49. exp Betaxolol/
50. (Betaxolol* or Kerlone or Kerlon or Oxodal or SL-75212 or SL75212 or ALO-1401-02 or ALO140102 or Betoptic or Betoptima or 63659-18-7).tw.
51. exp Adrenergic alpha-Agonists/
52. ((adrenergic adj2 alpha* adj3 agonist*) or (alpha* adj2 adrenergic adj3 agent*) or (alpha* adj2 adrenergic receptor) or (alpha* adj2 adrenergic adj2 stimula*) or (alpha* adj2 adrenoceptor adj2 stimula*) or (alpha* adj3 agonist) or alpha* sympathicomimetic or noradrenalin agonist* or noradrenergic agonist* or noradrenergic receptor stimulating agent*).tw.
53. exp Adrenergic alpha-2 Receptor Agonists/
54. exp Cholinergic Agonists/
55. ((Acetylcholine adj2 Agonist*) or cholinergic or cholinomimetic or parasympathetic agent* or parasympathetic drug* or parasympathomimetic or parasympathomimetics).tw.
56. exp Carbonic Anhydrase Inhibitors/
57. ((Carbonic adj2 Anhydrase adj2 Inhibitor*) or (Carbonate adj2 Dehydratase adj2 Inhibitor*) or (Carboxyanhydrase adj1 Inhibitor*)).tw.
58. exp Acetazolamide/
59. (Acetazolam* or Ak-Zol or AkZol or Apo-Acetazolamide or ApoAcetazolamide or Diacarb or Diamox or Diuramide or Defiltran or Edemox or Glauconox or Glaupax or Huma-Zolamide or HumaZolamide or Acetadiazol or 59-66-5).tw.
60. Brinzolamide.rn.
61. (Brinzolamide* or Azopt or 138890-62-7).tw.
62. Dorzolamide.rn.
63. (Dorzolamide* or MK-507 or Trusopt or L-671152 or 130693-82-2).tw.
64. isopropyl unoprostone.rn.
65. (isopropyl unoprostone* or unoprostone isopropyl or UF-021 or Rescula or Eescula or 69553-75-9).tw.
66. Brimonidine.rn.
67. (brimonidine* or bromoxidine or ratio-Brimonidine or Alphagan or UK-14,308 or UK-14304 or UK-14304-18 or AGN-190342 or 59803-98-4).tw.
68. or/26-67
69. exp eye/
70. exp eyelid/
71. exp Nasolacrimal Duct/
72. (ocular* or opthalm* or eye* or tear duct*).tw.
73. or/69-72
74. 68 and 73
75. 11 and 18 and (25 or 74)

The search filter for trials at the beginning of the MEDLINE strategy is from the published paper by Glanville et al (Glanville 2006).

Appendix 3. Appendix 3. EMBASE.com search strategy  

#1 'randomized controlled trial'/exp
#2 'randomization'/exp
#3 'double blind procedure'/exp
#4 'single blind procedure'/exp
#5 random*:ab,ti
#6 #1 OR #2 OR #3 OR #4 OR #5
#7 'animal'/exp OR 'animal experiment'/exp
#8 'human'/exp
#9 #7 AND #8
#10 #7 NOT #9
#11 #6 NOT #10
#12 'clinical trial'/exp
#13 (clin* NEAR/3 trial*):ab,ti
#14 ((singl* OR doubl* OR trebl* OR tripl*) NEAR/3 (blind* OR mask*)):ab,ti
#15 'placebo'/exp
#16 placebo*:ab,ti
#17 random*:ab,ti
#18 'experimental design'/exp
#19 'crossover procedure'/exp
#20 'control group'/exp
#21 'latin square design'/exp
#22 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21
#23 #22 NOT #10
#24 #23 NOT #11
#25 'comparative study'/exp
#26 'evaluation'/exp
#27 'prospective study'/exp
#28 control*:ab,ti OR prospectiv*:ab,ti OR volunteer*:ab,ti
#29 #25 OR #26 OR #27 OR #28
#30 #29 NOT #10
#31 #30 NOT (#11 OR #23)
#32 #11 OR #24 OR #31
#33 'glaucoma'/exp
#34 'intraocular hypertension'/exp
#35 glaucoma*:ab,ti
#36 ((intra*ocular OR 'intra ocular' OR ocular*) NEAR/3 (hypertension* OR tension* OR pressure*)):ab,ti
#37 iop:ab,ti
#38 #33 OR #34 OR #35 OR #36 OR #37
#39 'intraocular drug administration'/exp
#40 (ophthalm* NEAR/3 (instill* OR administ* OR solution*)):ab,ti
#41 'eye drops'/exp
#42 eye:ab,ti AND drop*:ab,ti OR eyedrop*:ab,ti
#43 ((clos* OR occlus* OR occlud*) NEAR/3 (eyelid* OR duct* OR lid*)):ab,ti OR elc:ab,ti
#44 ((nasolacrimal* OR 'tear duct') NEAR/3 (occlus* OR obstruct* OR occlud*)):ab,ti OR nlo:ab,ti
#45 #39 OR #40 OR #41 OR #42 OR #43 OR #44
#46 'topical drug administration'/de
#47 'drug instillation'/exp
#48 topical*:ab,ti OR drops*:ab,ti
#49 ((drug* OR medicat* OR medicin*) NEAR/3 (instill* OR administ*)):ab,ti
#50 (drop NEAR/2 (instill* OR administ*)):ab,ti
#51 'prostaglandin derivative'/exp
#52 'synthetic prostaglandins':ab,ti OR 'pg analogs':ab,ti OR 'prostaglandin analogues':ab,ti OR 'prostaglandin analogs':ab,ti OR dimethylprostaglandin:ab,ti OR methylprostaglandin:ab,ti OR 'prostaglandin 1':ab,ti
#53 'latanoprost'/exp
#54 latanoprost*:ab,ti OR phxa41:ab,ti OR xalatan:ab,ti OR phxa34:ab,ti OR '130209 82 4':ab,ti OR loutenor:ab,ti
#55 'travoprost'/exp
#56 travoprost*:ab,ti OR travatan:ab,ti OR 'al 6221':ab,ti OR al6221:ab,ti OR '157283 68 6':ab,ti OR 'fluprostenol isopropyl ester':ab,ti OR 'travatan z':ab,ti
#57 'bimatoprost'/exp
#58 bimatoprost*:ab,ti OR latisse:ab,ti OR lumigan:ab,ti OR agn192024:ab,ti OR 'agn 192024':ab,ti OR '155206 00 1':ab,ti
#59 'beta adrenergic receptor blocking agent'/exp
#60 'beta adrenergic antagonist':ab,ti OR 'beta adrenergic blocker':ab,ti OR 'beta adrenergic blockers':ab,ti OR 'beta adrenergic blocking agent':ab,ti OR 'beta adrenergic blocking drug':ab,ti OR 'beta adrenergic receptor antagonist':ab,ti OR 'beta adrenergic receptor blocker':ab,ti OR 'beta adrenoceptor antagonist':ab,ti OR 'beta adrenoceptor blocker':ab,ti OR 'beta adrenoceptor blocking agent':ab,ti OR 'beta adrenoceptor blocking drug':ab,ti OR 'beta adrenolytic':ab,ti OR 'beta adrenolytic agent':ab,ti OR 'beta antagonist':ab,ti OR 'beta antiadrenergic agent':ab,ti OR 'beta blocker':ab,ti OR 'beta blocking adrenergic agent':ab,ti OR 'beta blocking agent':ab,ti OR 'beta blocking drug':ab,ti OR 'beta receptor adrenergic blocking agent':ab,ti OR 'beta receptor blocker':ab,ti OR 'beta receptor blocking agent':ab,ti OR 'beta sympathicolytic agent':ab,ti OR 'beta sympathicolytics':ab,ti OR 'beta sympatholytic agent':ab,ti OR 'betasympatholytic agent':ab,ti
#61 'timolol'/exp
#62 timolol*:ab,ti OR timoptic:ab,ti OR timoptol:ab,ti OR timacar:ab,ti OR 'l 714465':ab,ti OR l714465:ab,ti OR 'mk 950':ab,ti OR mk950:ab,ti OR blocadren:ab,ti OR '26839 75 8':ab,ti OR 'apo timolol':ab,ti OR 'apo timol':ab,ti OR 'apo timop':ab,ti OR 'apotimol':ab,ti OR apotimolol:ab,ti OR apotimop:ab,ti OR betimol:ab,ti OR istalol:ab,ti OR moducren:ab,ti OR nyolol:ab,ti OR ofal:ab,ti OR ofan:ab,ti OR optimol:ab,ti OR timolo:ab,ti OR titol:ab,ti
#63 'metipranolol'/exp
#64 metipranolol*:ab,ti OR methypranol:ab,ti OR trimepranol:ab,ti OR disorat:ab,ti OR '22664 55 7':ab,ti OR 'beta ophtiole':ab,ti OR betalol:ab,ti OR betamann:ab,ti OR betamet:ab,ti OR betanol:ab,ti OR betanolol:ab,ti OR glauline:ab,ti OR 'normoglaucon mite':ab,ti OR ophtiole:ab,ti OR optipranolol:ab,ti
#65 'carteolol'/exp
#66 carteolol*:ab,ti OR opc1085:ab,ti OR '51781 06 7':ab,ti OR '51781 21 6':ab,ti OR arteolol:ab,ti OR arteoptic:ab,ti OR arteoptik:ab,ti OR caltamol:ab,ti OR calte:ab,ti OR carbonolol:ab,ti OR carteabak:ab,ti OR carteol:ab,ti OR cartrol:ab,ti OR 'catelon eye drop':ab,ti OR elebloc:ab,ti OR endak:ab,ti OR glauteolol:ab,ti OR karol:ab,ti OR karteol:ab,ti OR mikelan:ab,ti OR ocupress:ab,ti OR 'opc 1085':ab,ti OR stobol:ab,ti OR teoptic:ab,ti
#67 'levobunolol'/exp
#68 levobunolol*:ab,ti OR 'pms levobunolol':ab,ti OR pmslevobunolol:ab,ti OR 'ratio levobunolol':ab,ti OR ultracortenol:ab,ti OR vistagan:ab,ti OR 'w 6412a':ab,ti OR w6412a:ab,ti OR akbeta:ab,ti OR 'apo levobunolol':ab,ti OR apolevobunolol:ab,ti OR betagan:ab,ti OR bunolol:ab,ti OR 'novo levobunolol':ab,ti OR novolevobunolol:ab,ti OR w7000a:ab,ti OR '47141 42 4':ab,ti OR 'ak-beta':ab,ti OR 'ak beta':ab,ti OR betasite:ab,ti OR bunolgan:ab,ti OR gotensin:ab,ti OR 'w 7000a':ab,ti
#69 'betaxolol'/exp
#70 betaxolol*:ab,ti OR kerlone:ab,ti OR kerlon:ab,ti OR oxodal:ab,ti OR sl75212:ab,ti OR alo140102:ab,ti OR betoptic:ab,ti OR betoptima:ab,ti OR '63659 18 7':ab,ti OR 'alo 1401 02':ab,ti OR betac:ab,ti OR betarun:ab,ti OR betasel:ab,ti OR betaxon:ab,ti OR betoquin:ab,ti OR kerlong:ab,ti OR levobetaxolol:ab,ti OR lokren:ab,ti OR optibet:ab,ti OR optipress:ab,ti OR 'sl 75212':ab,ti OR tonobexol:ab,ti OR '72424 72 7':ab,ti OR '93221 48 8':ab,ti
#71 'alpha adrenergic receptor stimulating agent'/exp
#72 'adrenergic alpha-agonists':ab,ti OR 'adrenergic alpha agonists':ab,ti OR 'alpha adrenergic agent':ab,ti OR 'alpha adrenergic agonist':ab,ti OR 'alpha adrenergic receptor agent':ab,ti OR 'alpha adrenergic receptor agonist':ab,ti OR 'alpha adrenergic receptor stimulant':ab,ti OR 'alpha adrenergic receptor stimulator':ab,ti OR 'alpha adrenergic stimulant':ab,ti OR 'alpha adrenergic stimulating agent':ab,ti OR 'alpha adrenergic stimulator':ab,ti OR 'alpha adrenoceptor agonist':ab,ti OR 'alpha adrenoceptor stimulant':ab,ti OR 'alpha adrenoceptor stimulating agent':ab,ti OR 'alpha adrenoceptor stimulator':ab,ti OR 'alpha agonist':ab,ti OR 'alpha sympathicomimetic':ab,ti OR 'alpha sympathicomimetic agent':ab,ti OR 'noradrenalin agonist':ab,ti OR 'noradrenergic agonist':ab,ti OR 'noradrenergic receptor stimulating agent':ab,ti
#73 'alpha 2 adrenergic receptor stimulating agent'/exp
#74 'cholinergic receptor stimulating agent'/exp
#75 (acetylcholine NEAR/2 agonist*):ab,ti OR cholinergic:ab,ti OR cholinomimetic:ab,ti OR parasympathetic:ab,ti AND agent*:ab,ti OR parasympathetic:ab,ti AND drug:ab,ti OR parasympathetic:ab,ti AND drugs:ab,ti OR parasympathomimetic:ab,ti OR parasympathomimetics:ab,ti
#76 'carbonate dehydratase inhibitor'/exp
#77 'carboanhydrase inhibitor':ab,ti OR 'carbonic anhydrase inhibitor':ab,ti OR 'carbonate dehydratase inhibitor':ab,ti OR 'carboanhydrase inhibitors':ab,ti OR 'carbonic anhydrase inhibitors':ab,ti OR 'carbonate dehydratase inhibitors':ab,ti
#78 'acetazolamide'/exp
#79 acetazolam*:ab,ti OR 'ak zol':ab,ti OR akzol:ab,ti OR apoacetazolamide:ab,ti OR diacarb:ab,ti OR diamox:ab,ti OR diuramide:ab,ti OR edemox:ab,ti OR glauconox:ab,ti OR glaupax:ab,ti OR 'huma zolamide':ab,ti OR humazolamide:ab,ti OR '59 66 5':ab,ti OR '1424 27 7':ab,ti OR acetadiazol:ab,ti OR acetamox:ab,ti OR 'acetazol amide':ab,ti OR acetazoleamide:ab,ti OR acetozolamine:ab,ti OR albox:ab,ti OR 'apo acetazolamide':ab,ti OR azetazolamide:ab,ti OR carbinib:ab,ti OR cidamex:ab,ti OR dazamide:ab,ti OR defiltran:ab,ti OR dehydratin:ab,ti OR diluran:ab,ti OR diomax:ab,ti OR 'diuriwas wassermann barcelona':ab,ti OR diutazol:ab,ti OR eumicton:ab,ti OR fonurit:ab,ti OR genephamide:ab,ti OR glaucomed:ab,ti OR glaucomide:ab,ti OR ledamox:ab,ti OR lediamox:ab,ti OR ledimox:ab,ti OR natrionex:ab,ti OR nephramid:ab,ti OR novozolamide:ab,ti OR storzolamide:ab,ti OR ulcosilvanil:ab,ti OR ulcosylvanil:ab,ti
#80 'brinzolamide'/exp
#81 brinzolamide*:ab,ti OR azopt:ab,ti OR '138890 62 7':ab,ti OR 'al 4862':ab,ti OR al4862:ab,ti OR azoptic:ab,ti
#82 'dorzolamide'/exp
#83 dorzolamide*:ab,ti OR trusopt:ab,ti OR '130693 82 2':ab,ti OR biodrop:ab,ti OR 'l 671 152':ab,ti OR 'l 671152':ab,ti OR 'mk 13507':ab,ti OR 'mk 0507':ab,ti OR 'mk 507':ab,ti
#84 'unoprostone isopropyl ester'/exp
#85 (unoprostone NEAR/1 isopropyl*):ab,ti OR rescula:ab,ti OR eescula:ab,ti OR '69553 75 9':ab,ti OR '120373 24 2':ab,ti OR 'uf 021':ab,ti OR uf021:ab,ti
#86 'brimonidine'/exp
#87 brimonidine*:ab,ti OR bromoxidine:ab,ti OR 'ratio brimonidine':ab,ti OR alphagan:ab,ti OR 'uk 14308':ab,ti OR '59803 98 4':ab,ti OR 'agn 190342':ab,ti OR agn190342:ab,ti OR 'alphagan-p':ab,ti OR 'uk 14304':ab,ti OR 'uk 14304 18':ab,ti OR 'uk14304':ab,ti OR 'uk14304 18':ab,ti OR uk1430418:ab,ti
#88 #46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #60 OR #61 OR #62 OR #63 OR #64 OR #65 OR #66 OR #67 OR #68 OR #69 OR #70 OR #71 OR #72 OR #73 OR #74 OR #75 OR #76 OR #77 OR #78 OR #79 OR #80 OR #81 OR #82 OR #83 OR #84 OR #85 OR #86 OR #87
#89 'eye'/exp
#90 'eyelid'/exp
#91 'eyelid closure'/exp
#92 'lacrimal duct'/exp
#93 ocular*:ab,ti OR opthalm*:ab,ti OR eye*:ab,ti OR (tear NEAR/1 duct*):ab,ti
#94 #89 OR #90 OR #91 OR #92 OR #93
#95 #88 AND #94
#96 #32 AND #38 AND (#45 OR #95)

Appendix 4. Appendix 4. LILACS search strategy  

(Glaucoma$ or MH:C11.525.381$ or Ocular Hypertension or Hipertensión Ocular or Hipertensão Ocular or MH:C11.525$ or Intraocular Pressure or Presión Intraocular or Pressão Intra-Ocular or MH:G14.440$ or IOP or intraocular hypertension or intraocular tension or intraocular pressure or ocular tension or ocular pressure) AND ((Ophthalmic Administration or Administración Oftálmica or Administração Oftálmica or Ocular Administration or MH:E02.319.267.120.805$ or ((ophthalm$) and (instill$ or administ$ or solution$)) or Ophthalmic Solutions or Soluciones Oftálmicas or Soluções Oftálmicas or MH:D26.255.775.645$ or eyedrop$ or eyedrop or "eye drop" or "eye drops" or ((clos$ or occulus$ or occlude$) and (eyelid$ or duct$ or lid$ or nasolacrimal$)) or ELC or NLO) OR ((Topical$ or Tópica$ or drops or MH:E02.319.267.120$ or Drug Instillation or Instilación de Medicamentos or Instilação de Medicamentos or MH:E02.319.267.641$ or ((drug$ or medicat$ or medicin$ or drop) and (instill$ or administ$)) or Synthetic Prostaglandins or Prostaglandinas Sintéticas or MH:D10.251.355.255.550.700$ or PG Analogs or Prostaglandin Analogues or Prostaglandin Analogs or latanoprost$ or Xalatan or Travoprost$ or Travatan or bimatoprost$ or Lumigan or "Adrenergic beta Antagonists " or "Antagonistas Adrenérgicos beta" or "beta Adrenergic Receptor Blockader" or "beta Adrenergic Blocking Agent" or MH:D27.505.519.625.050.200.200$ or Timolol$ or MH:D02.033.100.624.915$ or Timoptic or Timoptol or Metipranolol$ or Trimepranol or MH:D02.033.100.624.545$ or Carteolol$ or MH:D02.033.100.624.210$ or Levobunolol$ or Bunolol or MH:D02.033.100.624.500$ or Betaxolol$ or Betoptic or MH: D02.033.100.624.102$ or "Adrenergic alpha Agonists" or "alpha Adrenergic Receptor Agonists" or "Adrenergic alpha Receptor Agonists" or MH:D27.505.519.625.050.100.100$ or "Adrenergic alpha 2 Receptor Agonists" or "Agonistas de Receptores Adrenérgicos alfa 2" or MH:D27.505.519.625.050.100.100.200$ or "Cholinergic Agonists" or "Agonistas Colinérgicos" or "Acetylcholine Agonists" or MH: D27.505.519.625.120.140$ or "Carbonic Anhydrase Inhibitors" or "Inhibidores de Anhidrasa Carbónica" or "Inibidores da Anidrase Carbônica" or "Carbonate Dehydratase Inhibitors" or MH:D27.505.519.389.200$ or Acetazolam$ or Diamox or MH: D02.886.675.867.060$ or Brinzolamide$ or Dorzolamide$ or Trusopt or isopropyl unoprostone$ or Rescula or brimonidine$ or Alphagan) AND (eye or Ojo or Olho or MH:A01.456.505.420$ or eyelids or Párpados or Pálpebras or MH:A01.456.505.420.504$ or Nasolacrimal Duct or Conducto Nasolagrimal or Ducto Nasolacrimal or MH:A09.371.463.640$ or ocular$ or opthalm$ or eye$ or tear duct$)) )

Appendix 5. Appendix 5. metaRegister of Controlled Trials search strategy

(Glaucoma OR glaucomas OR "ocular hypertension") AND ("Ophthalmic solution" OR Instillation OR Topical OR Topically OR "eyelid closure" OR "eye lid closure" OR "nasolacrimal occlusion" OR eyedrop OR eyedrops OR drops)

Appendix 6. Appendix 6. ClinicalTrials.gov search strategy

(condition) Glaucoma OR glaucomas OR "ocular hypertension"

(intervention)  "Ophthalmic solution" OR Instillation OR Topical OR Topically OR "eyelid closure" OR "eye lid closure" OR "nasolacrimal occlusion" OR eyedrop OR eyedrops OR drops

Appendix 7. Appendix 7. ICTRP search strategy

(condition) Glaucoma OR glaucomas OR ocular hypertension

(intervention)  Ophthalmic solution OR Instillation OR Topical OR Topically OR eyelid closure OR eyedrop OR eyedrops

Appendix 8. International Pharmaceutical Abstracts search strategy

S1 glaucoma*
S2 ((intra#ocular OR ocular*) AND (hypertension* OR tension* OR pressure*))
S3 IOP
S4 S1 OR S2 OR S3
S5 (ophthalm* AND (instill* OR administ* OR solution*))
S6 (eye drop* OR eyedrop*)
S7 (((clos* OR occlus* OR occlud*) AND (eyelid* OR duct* OR lid*)) OR ELC)
S8 (((nasolacrimal* OR 'tear duct') AND (occlus* OR obstruct* OR occlud*)) OR NLO)
S9 S5 OR S6 OR S7 OR S8
S10 topical* OR drops
S11 ((drug* OR medicat* OR medicin* OR topical) AND (instill* OR administ*))
S12 (Drop AND (instill* OR administ*))
S13 ("Synthetic Prostaglandins" OR "PG Analogs" OR "Prostaglandin Analogues" OR "Prostaglandin Analogs" OR dimethylprostaglandin OR methylprostaglandin OR "prostaglandin 1")
S14 (latanoprost* OR PHXA41 OR Xalatan OR PhXA34 OR 130209-82-4)
S15 (travoprost* OR Travatan OR AL-6221 OR AL6221 OR 157283-68-6)
S16 (bimatoprost* OR latisse OR Lumigan OR AGN192024)
S17 ((Adrenergic N1 beta* AND Blocker*) OR (Adrenergic AND beta* AND Blockader*) OR (beta* AND Adrenergic AND Blocking AND Agent*) OR (Adrenergic AND beta* AND Antagonist*) OR (beta* AND Adrenergic AND Blocking AND drug*) OR (beta* AND antagonist*) OR (beta* AND blocker*) OR (beta* AND blocking AND agent*) OR (beta AND blocking AND drug*) OR Beta* antiadrenergic agent* OR beta* sympathicolytic* OR beta* sympatholytic*)
S18 (Timolol* OR Timoptic OR Timoptol OR Timacar OR L-714,465 OR L714465 OR MK-950 OR MK950 OR Optimol OR Blocadren OR 26839-75-8)
S19 (Metipranolol* or Methypranol or Trimepranol or Disorat or 22664-55-7)
S20 (Carteolol* or OPC-1085 or OPC1085 or 51781-06-7)
S21 (Levobunolol* or PMS-Levobunolol or PMSLevobunolol or ratio-Levobunolol or Ultracortenol or Vistagan or W-6412A or W6412A or AKBeta or Apo-Levobunolol or ApoLevobunolol or Betagan or Bunolol or Novo-Levobunolol or NovoLevobunolol or W-7000A or W7000A or 47141-42-4)
S22 (Betaxolol* or Kerlone or Kerlon or Oxodal or SL-75212 or SL75212 or ALO-1401-02 or ALO140102 or Betoptic or Betoptima or 63659-18-7)
S23 ((adrenergic N2 alpha* N3 agonist*) or (alpha* N2 adrenergic N3 agent*) or (alpha* N2 adrenergic receptor) or (alpha* N2 adrenergic N2 stimula*) or (alpha* N2 adrenoceptor N2 stimula*) or (alpha* N3 agonist) or alpha* sympathicomimetic or noradrenalin agonist* or noradrenergic agonist* or noradrenergic receptor stimulating agent*)
S24 ((Acetylcholine N2 Agonist*) or cholinergic or cholinomimetic or parasympathetic agent* or parasympathetic drug* or parasympathomimetic or parasympathomimetics)
S25 ((Carbonic N2 Anhydrase N2 Inhibitor*) or (Carbonate N2 Dehydratase N2 Inhibitor*) or (Carboxyanhydrase N1 Inhibitor*))
S26 (Acetazolam* or Ak-Zol or AkZol or Apo-Acetazolamide or ApoAcetazolamide or Diacarb or Diamox or Diuramide or Defiltran or Edemox or Glauconox or Glaupax or Huma-Zolamide or HumaZolamide or Acetadiazol or 59-66-5)
S27 (Brinzolamide* or Azopt or 138890-62-7)
S28 (Dorzolamide* or MK-507 or Trusopt or L-671152 or 130693-82-2)
S29 (isopropyl unoprostone* or "unoprostone isopropy"l or UF-021 or Rescula or Eescula or 69553-75-9)
S30 (brimonidine* or bromoxidine or ratio-Brimonidine or Alphagan or UK-14,308 or UK-14304 or UK-14304-18 or AGN-190342 or 59803-98-4)
S31 S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 OR S23 OR S24 OR S25 OR S26 OR S27 OR S28 OR S29 OR S30
S32 (ocular* or opthalm* or eye* or eyelid or tear duct* or "nasolacrimal duct")
S33 S31 AND S32
S34 S4 AND (S9 OR S33)

Contributions of authors

LX developed, designed, and wrote the protocol. XM and MW provided feedback on the protocol.

Declarations of interest

None known.

Sources of support

Internal sources

  • Johns Hopkins University, Baltimore, Maryland, USA.

External sources

  • National Eye Institute, National Institutes of Health, Grant 1 U01 EY020522-01, USA.