THERAPEUTIC APPLICATION BROMFENAC ......2Shandong University Cheeloo College of Medicine, Jinan, China. 3St Teresa's College Ernakulam, M G University, Kerala, India. *Project Mentored

www.wjpps.com │ Vol 9, Issue 11, 2020. │ ISO 9001:2015 Certified Journal │

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Parvathi Rachita and Silpa. World Journal of Pharmacy and Pharmaceutical Sciences

THERAPEUTIC APPLICATION BROMFENAC, MOXIFLOXACIN

AND MOXI-DEXAMETHASONE IN EYE DISORDERS

1Parvathi M. L.,

2Rachita Kurmi and

3Silpa T. S.

1Mangalore University, Karnataka, India.

2Shandong University Cheeloo College of Medicine, Jinan, China.

3St Teresa's College Ernakulam, M G University, Kerala, India.

*Project Mentored by Bharat Kwatra, Invezion Labs.

Topical bromfenac for post-cataract extraction: A systematic

review and pooled analysis

The purpose of this pooled analysis is to investigate the safety and

efficacy of once daily Bromfenac for ocular inflammation and pain

among patients after cataract extraction (CE). Bromfenac, a promising

ophthalmic non-steroidal anti-inflammatory drug, has been shown to

be a safe and effective treatment for postoperative pain and

inflammation in subjects undergoing CE. Non-steroidal anti-

inflammatory drugs (NSAIDs) inhibit COXs so as to inhibit post-

operative pain and inflammation. It is becoming prevalent to begin NSAIDs dosing anywhere

from 1–2 days before surgery to reduce postoperative inflammation and pain.

Bromfenac, a highly potent inhibitor for both COX-1 and 2 isoforms, belongs to the NSAID

class but exhibits unique characteristics that enhances lipophilicity and facilitates its moving

across the epithelial layers and prolongs the duration of analgesic and anti-inflammatory

effect. These superior therapeutic benefits of Bromfenac have led to its ophthalmic use

especially for the pain and inflammation control after CE. Limiting the ocular exposure to

bromfenac may result in decreased adverse events (AEs), which is important because,

historically, ocular NSAID use has resulted in small numbers of corneal erosions or melts.

STUDY SELECTION- Any randomized controlled trial (RCT), controlled clinical trial

designed with at least two groups that one control group receiving vehicle-controlled

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 9, Issue 11, 580-622 Review Article ISSN 2278 – 4357

*Corresponding Author

Project Mentored by Bharat

Kwatra, Invezion Labs.

Article Received on

26 August 2020,

Revised on 15 Sept. 2020,

Accepted on 05 Oct. 2020

DOI: 10.20959/wjpps202011-17544


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ophthalmic solution, and the other receiving once- daily dosing of any type of topical

Bromfenac ophthalmic solution.

DATA SOURCES AND SEARCHES- The electronic databases screened were MEDLINE,

PsycINFO, Scopus, EMBASE, and The Cochrane Library (issue 9 of 12, September 2014)

from 1990 to September 2014.

OUTCOME MEASUREMENT- Primary efficacy outcomes were the proportion of cleared

ocular inflammation as determined by a summed ocular inflammation score (SOIS) of 0 and

ocular pain free. Postoperative ocular inflammation was measured by SOIS, and ocular pain

was evaluated by the ocular comfort grading assessment (OCGA) reported in the participants‟

diaries. Secondary efficacy outcomes were the drug- related reasons for discontinuation,

including adverse events, lack of efficacy, and receiving other rescue medication. Safety

outcomes were the common adverse events, including ocular inflammation, ocular pain,

foreign body sensation, and systemic adverse events. Pooled analyses of primary efficacy

outcomes.

Postoperative ocular inflammation: All trials reported the proportion of cleared ocular

inflammation as determined by an SOIS score of 0. The pooled analysis revealed that topical

bromfenac improved ocular inflammation within 15 postoperative days compared with

placebo. Postoperative ocular pain: All trials reported that the proportion of ocular pain free

was determined by an OCGA pain score of 0. The pooled analysis revealed that topical

bromfenac attenuated postoperative ocular pain within 15 days compared with

placebo. Pooled analyses of secondary efficacy outcomes.

Drug-related reasons for discontinuation: All trials reported the drug-related reasons for

discontinuation. The pooled analysis revealed that the patients in the topical bromfenac group

experienced less discontinuation because of adverse events. Pooled analyses of safety

outcomes: All studies reported the common adverse events including ocular inflammation,

ocular pain, foreign body sensation, and systemic adverse events in a total of 1690 patients.

The pooled analysis revealed that the patients in the topical bromfenac group experienced

fewer overall adverse events.

The utility of ophthalmic NSAIDs for the control of ocular inflammation, reduction of ocular

pain, as well as prevention and treatment of cystoid macular edema (CME) has been well


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documented in previous studies. Recently, Wang et al. and Sher et al.

reported on the role of

bromfenac in managing ocular pain and discomfort following refractive surgery.

The clinical benefits of bromfenac have been extensively discussed in several comparative

studies including the treatment of external or anterior ocular inflammatory diseases, allergic

conjunctivitis, as well as postoperative inflammation.

Bromfenac was found to be 3.7, 6.5, and 18 times more potent than diclofenac, amfenac,

and

ketorolac, respectively in inhibiting COX-2 activity. Although bromfenac and ketoroloc were

both well tolerated by patients undergoing laser in situ keratomileusis (LASIK), Epi-LASIK,

and laser- assisted subepithelial keratomileusis (LASEK), bromfenac was superior in

controlling postoperative pain. The pooled analysis demonstrated that the number of patients

with SOIS of 0 was significantly increased at postoperative day 3. The current pooled

analysis offers evidence for the safety and efficacy of topical bromfenac in reducing overall

ocular pain and inflammation during the whole postoperative period.

This pooled analysis came to the same that bromfenac is an effective treatment for

postoperative inflammation and pain after CE. However, since the merits of all studied RCTs

in the current analysis were weakened by the unreported demographics, co-morbidities of

study participants, and the potential bias, higher quality and more strictly controlled clinical

trials are required to identify the details of patients‟ outcome assessments, hospital costs, and

length of hospital stay, these possible sources of heterogeneity should be examined in future

clinical trials.

An ex vivo human aqueous humor-concentration comparison of two commercial

bromfenac formulations

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) have been used by cataract surgeons

for routine cases to reduce clinically significant cystoid macular edema (CME) and improve

early visual acuity. Clinically, NSAIDs are used by ophthalmologists in combination with or

instead of corticosteroids. The FDA has approved NSAID products in five indications:

seasonal allergic conjunctivitis, pain associated with cataract surgery, inflammation

associated with cataract surgery, pain associated with corneal refractive surgery, and

inhibition of intraoperative miosis. While not approved by the FDA specifically for this use,

NSAIDs are considered the standard of care by many anterior segment surgeons for

preventing CME associated with cataract surgery. More specifically, DuraSite is a synthetic


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polymer of cross-linked polyacrylic acid that stabilizes small molecules in an aqueous matrix.

Both nonclinical and clinical studies have shown the DuraSite drug- delivery system to be

safe and nontoxic. The increased time that DuraSite remains on the eye allows lower

concentrations of a given drug to be administered over a longer period. This offers

convenience of dosing, reduces the potential of adverse side effects, and may lead to

improved patient compliance.

The purpose of this study was to quantify the concentration of bromfenac in the aqueous

humor utilizing high-performance liquid chromatography mass spectrometry between two

commercial nonsteroidal anti-inflammatory drugs, using aqueous humor concentrations to

characterize pharmacokinetic proportional differences between 0.075% bromfenac

ophthalmic solution in DuraSite (BromSite®) and 0.09% bromfenac ophthalmic solution

(Bromday®

).

NSAIDs are believed to exert therapeutic effects based on in vivo concentrations, and if those

concentrations exceed the IC50 for COX1 and COX2 enzymes, and for what period of time.

NSAIDs are considered time-dependent inhibitors of COX1 and COX2. Therefore,

intraocular NSAID concentrations are expected to correlate with the efficacy of a given

topical ocular therapy.

DuraSite allows longer ocular surface-dwelling time for the bromfenac to absorb and exert its

NSAID therapeutic effects. Si et al described the tissue concentration of DuraSite containing

bromfenac was significantly higher than that of 0.09% bromfenac ophthalmic solution

(Xibrom) in all ocular matrices, excluding the retina.

Bromfenac delivered in DuraSite enhances the ocular bioavailability of bromfenac,

contributing to significantly higher NSAID concentrations in the aqueous humor compared to

bromfenac ophthalmic solution.

Comparative study of the efficacy and safety of bromfenac, nepafenac and diclofenac

sodium for the prevention of cystoid macular edema after phacoemulsification.

CME is the most frequent cause of visual loss after phacoemulsification. CME is normally a

subclinical and self-limited process, but in a small group of patients it turns into a chronic

process with permanent loss of visual acuity.


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The currently available topical non-steroidal anti-inflammatory drugs (NSAIDs) for

prevention and management of non-infectious ocular inflammation and CME in USA and

Europe include bromfenac, indomethacin, diclofenac, flurbiprofen, ketorolac tromethamine

and nepafenac. These drugs have been proven to be a safe and effective alternative to

corticosteroids in the topical prevention and management of CME. Miyake et al found that

diclofenac was more effective in preventing CME than a topical corticosteroid eyedrop,

fluorometholone. Indomethacin, among NSAIDs, has been used to prevent CME after

cataract surgery and has good intraocular bioavailability The aim of this research was to

compare the efficacy, tolerability and safety of bromfenac 0.09%, nepafenac 0.1% or

diclofenac 0.1% for the prophylaxis of the cystoid macular edema (CME) after

phacoemulsification. Macular thickness increases in 27% to 41% of eyes undergoing

phacoemulsification. Many studies assess the action of NSAIDs on the macular volume

regarding post- phacoemulsification CME prevention. Most of them conclude that even

though the little increase of the macular thickness following uncomplicated cataract surgery

is not clinically significant, the use of those drugs would be advisable after such operation to

ensure an excellent final visual acuity. However, there is no evidence about which of the

NSAIDs could be the most effective. Bromfenac is the most effective for the CME

prevention and nepafenac was the least effective. Nepafenac was the most effective and

bromfenac the least in reducing inflammation (through the Tyndall effect).Through patient

reported outcome survey, patients reported-Diclofenac achieved the highest reduction of pain,

and bromfenac, the lowest; Diclofenac reduced the blurred vision and foreign body sensation

the most. No patients using bromfenac reported a sticky eyes sensation. The drug which

caused the most ocular discomfort was diclofenac, and bromfenac was the one which caused

the least. The highest medication adherence was performed by patients in the bromfenac

group, and the lowest, by the diclofenac one. The highest satisfaction was reported by the

group that used nepafenac, and the lowest by the diclofenac group.

Combined use of corticosteroids with topical NSAIDs could reduce the latter‟s damaging

effect on the cornea. Topical NSAIDs may have harmful effects on the cornea, like

superficial punctate keratopathy, infiltrates, or corneal melting. In this study no corneal

adverse events were detected. The show that bromfenac 0.09% obtains a greater reduction of

the retinal thickness values, both at post- phacoemulsification 3-week and 2-month OCT

measurements. Patient‟s subjective satisfaction was highest with bromfenac 0.09%.

Regarding safety, no important adverse effect with any of the three drugs during the follow


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up period were recorded. Still it cannot be concluded which of the three drugs should be

preferentially used after cataract surgery, although it was found, bromfenac 0.09% was most

effective to reduce foveal thickness.

Anterior Chamber Inflammation After Cataract Surgery: A Randomized Clinical Trial

Comparing Bromfenac 0.09% to Dexamethasone 0.1%

Recently, ophthalmic non-steroidal anti-inflammatory drugs (NSAIDs) have received

attention as possible adjuvants to or substitutes for topical steroids after

phacoemulsification.[3]

Several advantages of NSAIDs over steroids have been claimed: they

do not induce changes in intraocular pressure (IOP); they may have a favorable

pharmacologic profile (fewer administrations); they may be more effective than steroids at re-

establishing the blood-ocular barrier after surgery; they can prevent pseudophakic cystoid

macular edema

The purpose of this study was to compare the anti-inflammatory effects of bromfenac 0.09%,

the most recently introduced ocular NSAID, to dexamethasone 0.1% as monotherapy for

2weeks. Postoperative inflammation was precisely evaluated by laser flare photometer with

close follow-up visits. Special attention was used to include a homogeneous population of

patients affected by senile cataract but with no other ocular comorbidities.

Phacoemulsification with IOL implantation was uncomplicated in all patients, with a similar

mean duration of surgery in both groups (13.89 ± 2.98 vs. 14.03 ± 2.95 min). Inflammation in

the anterior chamber in the two treatment groups described as time-to-event curves. The

event was defined as postoperative flare equal or inferior to the preoperative flare value. The

difference between the two treatments was not statistically significant at all time points.

As expected, in both treatment groups laser flare significantly increased the day after surgery

and decreased after starting the treatment. There was no statistically significant difference

between dexamethasone and bromfenac in terms of mean laser flare at all time points.

this clinical trial showed that bromfenac 0.09% was as effective as dexamethasone 0.1% in

reducing anterior chamber inflammation after cataract surgery.

One strength of the present study was the exact quantification of intraocular inflammation at

several time points after cataract surgery. One limit of the study was the absence of a

treatment group based on the combination of bromfenac and dexamethasone.


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This study presented new information on postoperative inflammation after uncomplicated

phacoemulsification. Not all the patients returned to their preoperative laser flare values 1

month after cataract surgery, suggesting that a 2-week treatment may be inadequate for some

patients. This long- lasting inflammation might explain the occurrence of pseudophakic

macular edema several weeks after uneventful cataract surgery in eyes that might have had

prolonged subclinical inflammation but appeared unremarkable at slit-lamp examination.

This clinical trial shed more light onto the controversy between ophthalmic NSAIDs and

steroids in the attempt to clarify their effect as monotherapy on anterior chamber

inflammation after routine cataract surgery. It indicates that modern tools to objectively

assess ocular inflammation should be included in future studies evaluating anti-inflammatory

treatments for ocular diseases.

Effect on Gel Formation Time of Adding Topical Ophthalmic Medications to ReSure

Sealant, an In Situ Hydrogel.

Although sutures to close cataract surgery incisions have been used and recommended for

imperfect wounds,12 infections have occurred despite sutures, and sutures may have even

been the nidus of the postoperative infections, even years after an uneventful surgery.

Various groups have reported on possible sealants, with one recently completing the rigorous

US Food and Drug Administration premarket approval (PMA) process to earn approval with

an indication to seal post cataract.

The pivotal study showed that the sealant is superior to suture in terms of fewer adverse

events and superior to preventing wound leaks (95.9% for sealant vs. 65.9% for sutures).

The purpose of this article was to describe the pharmacokinetics of gel formation of the

sealant, when used on label and when used off label by mixing with various standard topical

ophthalmic medications. In this experimental laboratory study, the commercial product,

ReSure Sealant, was used as per the product insert. Two drops of diluent were mixed with the

polymer and time to gel formation was measured. Following this, various commercial

antibiotic, nonsteroidal anti-inflammatory drug and steroid drops were used in substitution of

one of the drops of the diluent. Combinations of 2 medications were also tested. Each

condition was performed in triplicate and the mean gel time was calculated.


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ReSure Sealant is an in situ forming hydrogel that creates a temporary, soft, and lubricious

sealant to prevent fluid egress following cataract or IOL placement surgery. ReSure hydrogel

persists for approximately 1–3 days (up to 7 days in some cases), or until re-epithelialization

occurs. The cross- linked hydrogel is approximately 89% water at application. The hydrogel

is polyethylene glycol (PEG) based; PEG is commonly used in pharmaceutical, cosmetic, and

ophthalmic applications.

A novel way to possibly reduce the risk of microbes traversing incisions postoperatively, and

potentially reduce the rate of postoperative infections in cataract surgery, is sealing the entire

wound with a hydrogel. ReSure Sealant is a new FDA approved commercial polymer

hydrogel, which has been found to be superior to 10-0 nylon sutures in terms of sealing a

cataract surgery incision.

The data show that when the sealant was mixed with the fluoroquinolones MOX, OFX, GAT,

or CIP, it resulted in unacceptably long mean gel times of 105 s or longer.

The steroids LOT, DEX, and PRED also produced prolonged mean gel times from 83 s to

>120 s. The NSAID KET caused an increase in the gel time to 49 s, but the NSAID BROM

caused no increase, possibly even reducing the gel time (from 19 s to 13 s). What was more

remarkable was that when BROM was added to the fluoroquinolones MOX, GAT, or OFX,

the time to gel formation was substantially reduced compared with fluoroquinolones alone.

We hypothesize that elements of the BROM‟s formulation, such as elevated pH and the

presence of the amine group, caused the significant reduction of gel time even when added to

medications that alone increased the time to gel formation.

We tested BROM, KET, and NEP since these are the NSAIDs that are the most prescribed in

the United States. BROM improved not only the gel time when used alone but also more

surprisingly, decreased the time to gel formation when added to fluoroquinolone antibiotics

MOX, GAT, and OFX, producing gel times that would not substantially delay surgery.

The sealant, when mixed with a steroid, had a significantly increased gel time such that it

would not be practical to be considered in clinical practice. We did not mix the BROM with

the steroids DEX, PRED, and LOT in this study. This may be the focus of future studies.

Certain medications, specifically bromfenac, may not substantially alter time to gel formation

of ReSure Sealant when added to the hydrogel. In fact, bromfenac added to moxifloxacin,


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ofloxacin, or gatifloxacin reduced gel formation time to acceptable levels. All other

medications and combinations of medications added to ReSure Sealant produced

unacceptably long gel times to be used routinely. Clinical studies may be considered based on

these to assess the safety and efficacy of this strategy.

Topical Treatment With Bromfenac Reduces Retinal Gliosis and Inflammation After

Optic Nerve Crush

Although corticosteroids have a stronger anti-inflammatory effect than NSAIDs, they also

have various side effects and may trigger neuronal apoptosis and axonal loss. Therefore,

NSAID treatment is preferred, and these compounds are being extensively studied in patients

and animal models to assess their toxicity, pharmacokinetics, neuroprotective properties, and

anti-inflammatory and anti-edema effects, among others.

Kida et al. showed that compared to nepafenac and diclofenac, bromfenac concentration after

topical application on rabbit eyes was continuously higher in the retinochoroidal tissues.

Thus, bromfenac may have a better therapeutic effect than these two other NSAIDs in

retinochoroidal inflammatory diseases.

Regarding the therapeutic effect of bromfenac eye drops in animal models, it has been shown

that they reduce retinal edema triggered by lipopolysaccharide systemic injection in rats and

rabbits and prevent reactivation of herpes virus 1 in infected mice.

Thus, in this study the investigation is about the effect of topical bromfenac on retinal

degeneration, gliosis, and release of PGE2 in the rat retina after ONC.

Retinal Thickness

The retinal thickness decreased gradually, reaching statistical significance for both groups at

day 5 in the periphery, and closer to the optic disc in the bromfenac-treated group. Seven

days after the injury, the retina was significantly thinner in both groups and at both distances.

Interestingly, comparing both groups, the retina was thinner at day 7 in the bromfenac-treated

animals, reaching this difference statistical significance at 600 μm from the optic disc.

At 1200 μm from the optic disc, the thickness of RNFL significantly decreased by day 5 in

the bromfenac-treated group and at day 7 in both groups. At this latter time point, the RNFL

was significantly thinner in the treated versus untreated group. At 600 μm from the optic disc,

there were not significant changes in either group compared to baseline. However, 7 days


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after the lesion, the RNFL thickness was significantly reduced in the bromfenac-treated

retinas compared to untreated ones.

Bromfenac Treatment Does Not Accelerate Retinal Degeneration

Bromfenac treatment did not alter the number of Brn3a+RGCs, either in intact or in ONC-

injured retinas. Regarding CRALBP1(Muller cells), compared to intact retinas, its expression

declined after ONC but was maintained in ONC-treated samples. In intact but treated retinas,

CRABLP levels declined as well, although to a lesser extent than after ONC.

Retinal Gliosis

Optic nerve crush triggers a strong glial activation, which, at 7 days, almost reverted with

bromfenac treatment, as observed by immuno- detection and Western blotting. In retinal

extracts from intact animals treated during 7 days with bromfenac, Western blotting analysis

showed that GFAP and vimentin are upregulated compared to intact retinas, but their levels

are still lower than those found in ONC + bromfenac retinas.

Cyclooxygenases and Prostaglandin E2

Bromfenac mechanism of action is due to its ability to block prostaglandin synthesis by

inhibiting COX1 and COX2. Interestingly, in the ONC + bromfenac group, PGE2 levels were

reduced almost to the values found in intact retinas. Although recent work indicates that

bromfenac is more selective for COX2. Expression of COX2 is inducible in response to

injury and the release of cytokines and proinflammatory molecules, both of which occur in

the retina after ONC.

Interestingly, in spite of the increase of macroglial markers in intact + bromfenac retinas

compared to intact ones, the concentration of PGE2 was similar in both groups, suggesting

that perhaps the cytokines / inflammatory mediators that activate COX are released by

microglial cells.

The main findings of this work are that topical instillation of bromfenac (0.09%) reduces

retinal thickness, retinal gliosis, and the release of PGE2 after a complete intra-orbital ONC,

a drastic injury to the retina that in acute and massive RGC death. Importantly, bromfenac

treatment does not affect the number of RGCs in intact retinas or accelerate ONC- induced

degeneration. In fact, current experiments indicate that bromfenac treatment increases RGC


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survival after ONC, although this protection is not immediate but is delayed to 9 days onward

(Rovere G, Nadal-Nicol as FM, Vidal-Sanz M, Agudo-Barriuso, M. unpublished data, 2016).

Besides reducing gliosis, bromfenac abolishes the release of PGE2, which in turn may

effectively reduce the retinal edema, since prostaglandins in the eye disrupt the blood–ocular

barrier, increase vasodilation, and facilitate leukocyte migration causing edema and

inflammation.

If this hypothesis is sustained, it would be of interest to instill NSAIDs in patients with retinal

edema when diagnosed by in vivo measurement of the retina.

Topical administration of bromfenac is an efficient and non-invasive treatment to control the

retinal gliosis and release of proinflammatory mediators that follow a massive insult to the

RGC population.

Management of ocular inflammation and pain following cataract surgery: focus on

Bromfenac ophthalmic solution

Studies have shown that bromfenac ophthalmic solution 0.09% has equivalent efficacy to the

other topical NSAIDs in reducing postsurgical inflammation and controlling pain. The unique

chemical structure of bromfenac makes it both a potent inhibitor of the COX-2 enzyme and a

highly lipophilic molecule that rapidly penetrates to produce early and sustained drug levels

in all ocular tissues. Bromfenac ophthalmic solution 0.09% is a versatile agent and is

effective when used as either monotherapy or as an adjunct therapy to steroids.

Classification of NSAIDs

Topical NSAIDs are classified into six groups based on their chemical composition: indoles,

phenylacetic acids, phenylalkanoic acids, salicylates, fenamates, and pyrazolones.

Introduction to Bromfenac

Bromfenac sodium ophthalmic solution 0.1% was first approved in May 2000 as Bronuck®

(Senju Pharmaceutical Company, Ltd., Osaka, Japan) and is presently approved by the

Ministry of Health in Japan for the clinical indications of the treatment of postoperative

inflammation, blepharitis, conjunctivitis and scleritis. The recommended dosage of

bromfenac ophthalmic solution 0.09% is one drop in the affected eye(s) twice daily beginning

24 hours after cataract surgery and continuing through the first 2 weeks of the postoperative

period.


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Pharmacology of bromfenac-Chemistry

Bromfenac sodium is designated chemically as sodium 2-amino-3-(4-bromobenzoyl)

phenylacetate sesquihydrate, with an empirical formula of C15H11BrNNaO.11⁄2 H2 0.

Structure of bromfenac is identical to amfenac, with the key exception of a bromine atom at

the C4 position.

Pharmacodynamics of bromfenac vs nepafenac/amfenac vs ketorolac

Walters et al researched the in vivo pharmacokinetics and in vitro pharmacodynamics of

nepafenac, amfenac, ketorolac, and bromfenac. Seventy-five patients participated in this

study and Walters et al determined that nepafenac showed significantly greater ocular

bioavailability and greater potent COX-1 inhibition than any other drug tested and amfenac

demonstrated greater potency and COX-2 inhibition than ketorolac or bromfenac.

COX inhibition of bromfenac vs ketorolac -Another study analysing NSAID COX

inhibitory activities compared the COX inhibitory activity and ocular anti- inflammatory

effects of ketorolac and bromfenac. The authors reported that ketorolac inhibited COX-1

more strongly than bromfenac while bromfenac had greater COX-2 inhibitory activity than

ketorolac.

Bromfenac vs diclofenac ophthalmic solution-Several subsequent clinical studies have

compared the efficacy of bromfenac ophthalmic solution with diclofenac ophthalmic solution

in reducing inflammation after cataract surgery.

Safety and tolerability of bromfenac ophthalmic solution-Subjects in clinical trials of

long-term treatment with the oral bromfenac were found to have an increased incidence of

liver enzyme elevations. While there were no cases of serious liver injury, the FDA

prescribing information for oral bromfenac was subsequently amended to include a re-

emphasized “black box” warning limiting use to no more than 10 days.

Adverse effects of bromfenac-The most common adverse events reported with bromfenac

included abnormal sensation in the eye, conjunctival hyperemia, eye irritation (including

burning/stinging), eye pain, eye pruritis, eye redness, headache, and iritis. No deaths have

been reported with bromfenac 0.09% ophthalmic solution. The rapid onset of bromfenac in

the treatment of postsurgical inflammation diminishes ocular irritation, including burning and

stinging. Reports of serious and no serious adverse effects have been low since drug approval


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and there have been no reports of liver toxicity according to the post- marketing safety

surveillance data available.

Bromfenac vs ketorolac vs diclofenac for the treatment of acute pseudophakia CME-

Rho et al presented of a study comparing bromfenac ophthalmic solution with diclofenac and

ketorolac for the treatment of acute pseudophakia CME. there was a trend toward

significance for the bromfenac group. Rho concluded that twice-daily bromfenac was

statistically as effective as diclofenac or ketorolac dosed 4 times daily.

Bromfenac for the treatment of allergic conjunctivitis-Bromfenac ophthalmic solution

was compared with the ophthalmic mast cell stabilizer pemirolast potassium for the treatment

of seasonal allergic conjunctivitis in a clinical study by Miyake Kashima et al. Both drugs

improved 4 of 5 objective signs but there was no significant difference between the drugs in

objective efficacy. Neither drug significantly improved subjective symptoms after this brief

treatment period nor was there any difference between them in the subjects‟ assessment.

Bromfenac for the treatment of anterior uveitis-Usui and Masude reported on the

evaluation of twice-daily bromfenac ophthalmic solution for the treatment of anterior uveitis

over both 2-week and 12-week treatment courses. The investigators concluded that

bromfenac seemed to reduce inflammation associated with anterior uveitis with minimal side

effects, potentially providing a safer alternative to long- term treatment with ophthalmic

steroids.

In multiple comparative trials, bromfenac ophthalmic solution 0.09% has been shown to

provide safe and effective relief of perioperative inflammation and pain following cataract

surgery. Clinically, these pharmacokinetic features are manifested in a rapid reduction of

postsurgical inflammation and pain with bid dosing. Further clinical investigations will

explore the expanding use of bromfenac in a variety of other clinical settings, including, but

not limited to, the management of ocular inflammation and pain following cataract surgery.

Prophylactic non-steroidal anti-inflammatory drugs for the prevention of macular

oedema after cataract surgery

Macular oedema (MO) is the accumulation of extracellular fluid in the central retina (the

macula). It may occur after cataract surgery and may give rise to poor visual outcome, with

reduced visual acuity and distortion of the central vision. MO is often self-limiting with


593


spontaneous resolution, but a small proportion of people with chronic persistent MO may be

difficult to treat. Chronic oedema may lead to the formation of cystic spaces in the retina

termed 'cystoid macular oedema' (CMO). Non-steroidal anti-inflammatory drugs (NSAIDs)

are commonly used in cataract surgery and may reduce the chances of developing MO.

The aim is to answer the question: is there evidence to support the prophylactic use of topical

NSAIDs either in addition to, or instead of, topical steroids postoperatively to reduce the

incidence of macular oedema (MO) and associated visual morbidity.

Randomised controlled trials (RCTs) were included in which adult participants had

undergone surgery for age-related cataract. Participants irrespective of their baseline risk of

MO were included, in particular included people with diabetes and uveitis were included.

Trials of preoperative and/or postoperative topical NSAIDs in conjunction with postoperative

topical steroids were also taken into consideration. The comparator was postoperative topical

steroids alone. A secondary comparison was preoperative and/or postoperative topical

NSAIDs alone versus postoperative topical steroids alone.

The review authors found 34 relevant studies. These studies were conducted in all parts of the

world including the Americas, Europe, the Eastern Mediterranean region and South-East

Asia. Most (28) of these studies compared NSAIDs combined with steroids against steroids

alone. Some of the studies (6) compared NSAIDs with steroids alone. A variety of NSAIDs

were used, including ketorolac, diclofenac, nepafenac, indomethacin, bromfenac, pranopfen

and flurbiprofen. People taking part in these trials were followed up from between one and 12

months. Most studies only followed up to two months or less. Six studies were funded by

industry; seven studies were funded from non-industry sources and the rest of the studies did

not report the source of funding.

There was low-certainty evidence that NSAIDs reduce the chance of poor vision due to

macular oedema three months after cataract surgery.

Only one study reported on poor vision due to macular oedema at 12 months and we judged

this to have very low-certainty of evidence.

Using NSAIDs was associated with a reduced risk of macular oedema but the review authors

judged this to be low-certainty.


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Inconsistent were seen for some measurements of macular oedema, such as the thickness of

the tissue at the back of the eye (central retinal thickness) at three months after surgery. This

measurement was not reported by any studies at 12 months after surgery.

Similarly, inconsistent were seen for vision measurement (visual acuity) but most studies

found small differences between people given NSAIDs and people not given NSAIDs.

Only one study reported quality of life, and this suggested little impact of NSAIDs on quality

of life. Adverse events mainly consisted of a burning or stinging sensation.

Using topical NSAIDs may reduce the risk of developing macular oedema after cataract

surgery, although it is possible that current estimates as to the size of this reduction are

exaggerated. It is unclear the extent to which this reduction has an impact on the visual

function and quality of life of patients.

There is little evidence to suggest any important effect on vision after surgery. The value of

adding topical NSAIDs to steroids, or using them as an alternative to topical steroids, with a

view to reducing the risk of poor visual outcome after cataract surgery is therefore uncertain.

Future trials should address the remaining clinical uncertainty of whether prophylactic topical

NSAIDs are of benefit, particularly with respect to longer-term follow-up (at least to 12

months), and should be large enough to detect reduction in the risk of the outcome of most

interest to patients, which is chronic macular oedema leading to visual loss.

24-Hour Evaluation of the Ocular Distribution of 14C-Labeled Bromfenac Following

Topical Instillation into the Eyes of New Zealand White Rabbits

The octanol/water (O/W) partition coefficient (Clog P) and the quantitative structure-activity

relationship (QSAR) of a drug is another factor that influences its penetration properties and,

consequently, its potency. Clog P estimates the water solubility and the level of lipophilicity

of a compound (a key determinant of the pharmacokinetics parameter).

It is commonly used in drug-design studies, since this property is related to drug absorption,

bioavailability, metabolism, and toxicity. The higher the value, the better the penetration,

with a 1.0-unit difference in the coefficient representing a tenfold difference in penetration.

Ruiz et al.6 reported that the Clog P of bromfenac (2.23) is higher than other NSAIDs, such

as amfenac (1.23) and ketorolac (1.88). This difference in Clog P explains the higher


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lipophilicity of bromfenac that provides a more rapid saturation of the epithelium and a

minimal lag time before the drug crosses the cornea and, thus, the fast analgesic action.

The aim of this preclinical investigation was to evaluate the penetration of 14C-bromfenac

following a single ocular instillation in New Zealand White (NZW) rabbit eyes.

A single 50-μL 14

C-bromfenac ophthalmic solution (20–25μ Ci or 0.09%) was administered

into the right eyes of 14–18 randomly assigned NZW rabbits. At various time points, ocular

tissues were collected and analyzed for 14

C-bromfenac contents. Ocular tissues were

combusted and the amount of radioactivity was determined by liquid scintillation counting

(LSC). Aqueous humor samples were directly transferred to LSC vials.

The first study had 14 NZW rabbits randomized into seven groups of 2 rabbits each. The

second study had 18 NZW rabbits randomized into six groups of 3 rabbits each.

The first study was designed to ensure that enough measurable radiolabelled bromfenac was

available. The second study tested commercial-strength bromfenac ophthalmic solution

0.09%.

The radioactivity present in the conjunctiva of 2 dosed eyes in group G (first study) varied

greatly, indicating a possible contamination. Consequently, the samples were excluded.

Excessive tearing occurred in 1 animal in group E, of the same study, following dosing.

Duplicate aliquots (25 μL) of each sample were analyzed by LSC. The radioactivity present

in each wipe was considered as radioactivity lost during dosing, and actual administered

doses were calculated accordingly.

Peak concentrations of radiolabelled bromfenac were observed in all ocular tissues in the first

study at 2 h, with the exception of the conjunctiva, which showed peak tissue concentration at

1 h, and the lens, which showed peak tissue concentration at 3 h (Table 2).

In the second study, peak concentrations of radiolabelled bromfenac were observed in all

ocular tissues at 1–2 h, with the exception of the lens and vitreous humor (Table 3).

The bromfenac concentrations were highest in the cornea. Similar amounts of radiolabelled

bromfenac were measured in the aqueous humor, iris-ciliary body, choroid, and, to a slightly

lesser degree, the retina. Further, radiolabelled bromfenac was detected in all samples 24 h


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following topical administration in the first and second studies, with the exception of the

vitreous humor.

In addition to potency, another important criterion of topical anti-inflammatory drugs is the

ability to penetrate the tissues to reach their target(s) in a timely manner and appropriate

concentration. Thus, the ability to penetrate ocular tissues is an important determinant of the

safety and efficacy of ophthalmic NSAIDs.

The two animal studies presented in this report demonstrate that a single topical dose of

commercial-strength bromfenac ophthalmic solution 0.09% rapidly, within 2 h, achieved

measurable levels in all ocular tissues and detectable levels were sustained over 24 h.

One unexpected finding revealed that, unlike other ocular tissues, radiolabelled bromfenac

was undetectable in the vitreous humor after 1 h.

Topical bromfenac reduces the frequency of intravitreal bevacizumab in patients with

branch retinal vein occlusion

Branch retinal vein occlusion (BRVO) is the second most frequent major retinal vascular

disease after diabetic retinopathy. Macular oedema (ME) develops in ∼60% of eyes with a

BRVO and is one of the major causes for visual loss in eyes with BRVO.

An earlier study on the natural history of BRVO reported that only 14% of eyes with chronic

ME secondary to BRVO retained a visual acuity (VA) of 20/40 or better, whereas 86% had a

final VA of 20/50 or worse. Topical bromfenac, a non-steroidal anti-inflammatory drug

(NSAID) in combination with anti-VEGF antibody therapy for age-related macular

degeneration, showed a synergistic effect with improved anatomical, functional outcomes and

the need for fewer intravitreal injections.

In this study, the efficacy of topical bromfenac in reducing the number of IVB treatments for

ME secondary to BRVO was investigated to determine the number of injections of IVB

necessary to maintain the morphological resolution of ME and to evaluate the clinical course

of visual function.

Prospective interventional case–control study. 48 eyes of 44 patients with ME-BRVO who

received 1.25 mg/0.05 mL of IVB showed temporary regression of ME. Additional IVB were

given when ME recurred. 24 eyes received topical bromfenac, and the other 24 eyes received


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topical saline as control, four times a day during the clinical course of 48 weeks. The clinical

course of foveal thickness (FT) as measured by optical coherence tomography, logarithm of

the minimum angle of resolution visual acuity (VA), was monitored. The number of IVB was

also recorded.

Initial IVB treatment was performed in all 50 eyes. Two eyes belonging to the „not effective‟

group were identified during the first 3 months. Also, eight of the 48 „effective‟ eyes did not

show a recurrence of ME. Thus, 40 eyes were identified as „effective with recurrence‟ and

were eligible for further case– control study. All 40 of the „effective with recurrence‟ eyes

identified after the initial bevacizumab injection received a second injection. Following the

second injection, 20 eyes had continuous topical bromfenac and the other 20 eyes were

observed as controls. There were no significant differences in gender, age, preclinical period,

initial FT and initial VA between the topical bromfenac group and the control group.

Does topical bromfenac affect „effective with recurrence‟ eyes?

During the clinical course, improvement in VA in the topical bromfenac groups was

−0.447±0.122, which was not significantly different from that in the control group of

−0.437±0.096 (p=0.867).

In this prospective case–control study, compared with IVB mono therapy, adjunctive therapy

with topical bromfenac did not have a significant effect on functional and morphological

resolution, while this combination therapy was found to reduce the number of IVB injections

to maintain FT under 300μm within a 1-year follow-up period.

The frequency of the anti-VEGF drug injections represents an economic burden for patients

and society and is possibly associated with serious complications such as endophthalmitis and

arteriothrombotic events.

In this prospective study, although bromfenac, a topical NSAID, did not augment the

reduction effect by IVB, it did extend its effect to reduce the frequency of IVB over a 1-year

follow-up.

Actually, the duration of topical bromfenac in this study was <1 year because the topical

application was started after the confirmation of recurrence of ME at month 3, thus longer

application may bring more prominent.


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The anti-VEGF drug bevacizumab suppressed hyper-vascular permeability, while a topical

NSAID of bromfenac suppressed inflammatory conditions. Both hyper-vascular permeability

and tissue inflammation worsen tissue oedema; thus, it is not surprising that this combination

therapy has a beneficial effect for ME secondary to BRVO.

Although topical bromfenac during IVB therapy in eyes with ME secondary to BRVO did not

affect the visual prognosis, it had the advantage of reducing the number of injections.

Clinical Trials: Bromfenac

Prolensa (Bromfenac) 0.07% QD vs. Ilevro (Nepafenac) 0.3% QD for Treatment of Ocular

Inflammation Post Cataract Surgery (QD)

ClinicalTrials.gov Identifier: NCT01847638

With an interventional and randomized study design, enrolling 50 participants, the purpose of

this clinical trial was to investigate the clinical outcomes for inflammation, visual acuity and

macular thickness after treatment with Prolensa (bromfenac ophthalmic solution) 0.07% QD

in subjects who have undergone cataract extraction with posterior chamber intraocular lens

implantation.

The safety and efficacy of these two compounds in patients undergoing cataract surgery has

been thoroughly examined in independent studies, however, head-to-head data comparing

postoperative outcomes with the two products are limited.

Primary Outcome Measure-Treatment of Inflammation Associated With Cataract Surgery

[Time Frame: change from baseline to final at post op 42 days +/-7 days]

Secondary Outcome Measure-Visual Acuity [Time Frame: baseline score to final

postoperative visit at 42 days +/-7 days]

Other Outcome Measures-Retinal Thickness [Time Frame: change from baseline to final

postoperative visit at 42 days +/- 7 days]

Both, bromfenac 0.07% ophthalmic solution and nepafenac 0.3% ophthalmic suspension,

showed similar efficacy and tolerability in minimizing post-surgical inflammation and retinal

thickening.


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Positive and similar were observed with regard to [Early Treatment Diabetic Retinopathy

Study]ETDRS visual acuity post-cataract surgery. Comparisons in mean retinal thickness and

mean macular volume were made between the two ophthalmic solutions and the increase was

similar and minute.

Comparison Study of ISV-303 to DuraSite Vehicle in Cataract Surgery Subjects (ISV-303)


The following study is A multicenter, double-masked, vehicle-controlled, parallel-group

clinical trial of 268 subjects randomized in a 2:1 ratio to bromfenac 0.075% or vehicle was

conducted. The aim was to evaluate the ocular safety, tolerability, and efficacy of topical

administration of ISV-303 compared with DuraSite Vehicle.

At all time points, there was a significant difference between the bromfenac 0.075%-treated

group and the vehicle-treated group .

At each of the postsurgical time points (Days 1, 8, 15, and 29), proportionally more

bromfenac 0.075%-treated subjects (76.8%, 90.5%, 92.9%, and 85.1%, respectively) had no

pain (a VAS score of 0) comparing to the vehicle-treated subjects (48.2%, 38.8%,42.4%, and

47.1%, respectively), and at each time point, these differences in proportions were

statistically significant (P<0.001).

More subjects in the bromfenac 0.075% group had complete ACF resolution (151/167;

90.4%) compared to those in the vehicle group (54/85; 63.5%). There were no new safety

signals reported.

More subjects in the vehicle group had severe TEAEs compared to those in the bromfenac

0.075% group (7.1% [6/85] vs 1.8% [3/169], respectively).

This study shows that bromfenac 0.075% in DuraSite is safe, well tolerated, and effective at

reducing inflammation and preventing pain associated with cataract surgery and confirms that

bromfenac 0.075% reduced inflammation better than the currently marketed versions of

bromfenac in both once- and twice-daily formulations.


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Efficacy and Safety of Bromfenac Ophthalmic Solution in Cataract Surgery(2008) &

Efficacy Study of Bromfenac Ophthalmic Solution in Patients Undergoing Cataract

Surgery(2009)Information provided by (Responsible Party).



A total of 455 subjects (455 study eyes: 230 bromfenac, 225 placebo) were enrolled in two

randomized double-masked, placebo-controlled, clinical trials at 64 ophthalmology clinics to

evaluate Efficacy and Safety of Bromfenac Ophthalmic Solution 0.09% in Cataract Surgery.

The mean SOIS for the bromfenac 0.09% group was lower than the placebo group at Days 3,

8, 15, and 22 (P < 0.0001). More bromfenac 0.09% subjects were pain free at Days 1, 3, 8,

and 15 (P < 0.0001).

Bromfenac ophthalmic solution 0.09% dosed once daily is clinically safe and effective for the

treatment of ocular inflammation and the reduction of ocular pain associated with cataract

surgery.

Aqueous Humor Concentration of InSite Vision (ISV) 303 (Bromfenac in DuraSite) to

Bromday Once Daily (QD) Prior to Cataract Surgery.


This multi-center, randomized, double-masked, 2-arm, parallel-group, comparative clinical

trial of 60 subjects was done To compare the aqueous humor penetration of two different

formulations of Bromfenac, namely commercial Bromday (0.09%) with Bromfenac in

DuraSite (0.075%).

Study showed that the mean concentration of bromfenac in the aqueous humor of subjects in

the ISV-303 treatment group was more than twice greater compared to those subjects dosed

with Bromday.

There were no adverse events reported in this study and no safety concerns for either of the 2

treatment groups.

Therapeutic concentrations of bromfenac are very necessary to prevent pain and regulate

inflammation of anterior and the posterior ocular tissues, and this study confirmed superior


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tissue penetration of ISV-303 against the market leader, Bromday, to reduce the pain and

inflammation associated with ocular surgery.

A Comparison of Prostaglandin E2 (PGE2) Inhibition of Acuvail (Ketorolac 0.45%), Xibrom

(Bromfenac 0.09%)and Nevanac (Nepafenac)in Patients Undergoing Phacoemulsification


This interventional randomized clinical trial of 126 participants was done to compare the

PGE2 inhibition of three topical NSAIDs - ketorolac 0.45% (Acuvail), bromfenac 0.09%

(Xibrom), and nepafenac 0.1% (Nevanac) in patients undergoing phacoemulsification at peak

dosing levels. Study show that The mean PGE2 values were 224.8 +/-164.87 pg/ml for

ketorolac (n=42), 288.7 +/-226.05 pg/ml for bromfenac (n=42), and 320.4 +/-205.6 pg/ml for

nepafenac (n=42).No adverse events or safety concerns were reported. Difference between

Bromfenac and Nepafenac is not so significantly different, while between Ketorolac and

Nepafenac the difference is quite large being in favour of Ketorolac. Similarly, between

Bromfenac and Ketorolac the difference is statistically visible and in favour of Ketorolac.

This new ketorolac compound achieved the greatest inhibition of PGE2 compared to

nepafenac 0.1% and bromfenac 0.09%. Thus it can be concluded that Ketorolac 0.45% is

more efficient in inhibition of PGE2 and controlling ocular inflammation at the time of

surgery than Bromfenac 0.09% and Nepafenac 0.1%.

A Comparison of Peak Aqueous Penetration of Acuvail (Ketorolac 0.45%), Xibrom

(Bromfenac 0.09%), and Nevanac (Nepafenac 0.1%)in Patients Undergoing

Phacoemulsification.


The purpose of this interventional, randomized clinical trial of 126 participants was to

compare the peak to-aqueous penetration of three nonsteroidal anti-inflammatory drugs:

ketorolac tromethamine 0.45%, bromfenac 0.09% and nepafenac 0.1% in patients undergoing

phacoemulsification.

The peak aqueous concentration of ketorolac 0.45% was 10 times the concentration of

bromfenac 0.09%. The mean peak aqueous concentration of ketorolac 0.45% was

688.87 ± 749.6 ng/ml. Bromfenac achieved a mean peak aqueous concentration of


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67.64 ± 62.4 ng/ml. While mean peak aqueous concentrations of nepafenac reached till

447.10 ± 225.7 ng/ml.

The peak concentration of ketorolac was thus statistically significantly greater than

bromfenac and nepafenac as it achieved dramatically greater aqueous concentrations.

Thus ketorolac has high efficacy to treat pain and post-surgery ocular inflammation.

Therapeutic Applications of Moxifloxacin

1) Review of moxifloxacin hydrochloride ophthalmic solution in the treatment of

bacterial eye infections

Moxifloxacin hydrochloride ophthalmic solution 0.5% is the ocular formulation/adaptation of

moxifloxacin. Moxifloxacin is a broad spectrum, 8-methoxy fluoroquinolone is an

antibacterial agent which is concentration dependent with improved anti- infective activity

against bacterial infections. Moxifloxacin hydrochloride ophthalmic solution 0.5 is an

isotonic, preservative free solution used for the treatment of bacterial conjunctivitis, keratitis

and surgical prophylaxis. Modification of the moxifloxacin core molecule inhibit the bacterial

growth by binding to DNA gyrase (topoisomerase II) and topoisomerase IV. DNA gyrase and

topoisomerase IV are essential bacterial enzymes involved in the replication, translation,

repair and recombination of deoxyribonucleic acid. Inhibition of either of these enzymes will

leads to bacteria death. Affinity for both enzymes improves potency and reduces the

probability of selecting resistant bacterial subpopulations. In vitro and clinical studies

indicates that the moxifloxacin treatment is safe in childrens (3 days to 17 years) and adults

(up to age 93). Moxifloxacin was significantly more tolerable in healthy adult and pediatric

eyes. Adverse events including conjunctivitis, keratitis and endophthalmitis have been low

after moxifloxacin treatment. Moxifloxacin hydrochloride ophthalmic solution 0.5% have

moderately high rate of clinical success against common ocular pathogens.

2) An assessment of the tolerability of moxifloxacin 0.5% compared to azithromycin

1.0% in Moxifloxacin

Moxifloxacin 0.5% ophthalmic solution is a broad spectrum which is concentration-

dependent and highly effective against bacterial infections. While azithromycin is

bacteriostatic and time-dependent. Depending on the concentration, azithromycin show high

level of Gram-positive resistance patterns. The purpose of this study was to compare subjects

perceptions of moxifloxacin and azithromycin in healthy adult and pediatric subjects. One

hundred and twenty-five healthy volunteers with normal ocular health were selected for the


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study. It is a single center, single-visit, subject-masked, randomized, active, and placebo-

controlled study. A trained technician instilled one drop of moxifloxacin and azithromycin in

the eyes of healthy adults and pediatric populations. Drops were installed in different time

points (0, 1, 3, 5, and 10 minutes). After instillation, subjects rated comfort, acceptability, and

blurring on 0–10 point analog scales stating their preference of treatment at different time

points. There was a significant preference for moxifloxacin over azithromycin at every time

point (p ≤ 0.0001 and p ≤ 0.0002, respectively) in both pediatric and adult subjects . An

average of 84% of all subjects and 82% of pediatric subjects preferred moxifloxacin over

azithromycin. Moxifloxacin was found to be more comfortable (p < 0.0001), acceptable (p <

0.0001), and resulted in less blurring (p < 0.0001) than azithromycin at every time point.

Some adverse events were also observed during the study. One subject receiving

moxifloxacin experienced 2 ocular adverse events and 18 subjects receiving azithromycin

experienced 25 adverse events. Moxifloxacin resulted in less blurred vision and was more

comfortable and acceptable to subjects than azithromycin. Azithromycin was less tolerable

than moxifloxacin because of the more adverse events.

3) Application of intracameral moxifloxacin to prevent endophthalmitis in cataract

surgery

Endophthalmitis is a serious complication of cataract surgery that can lead to severe visual

loss. It is a rare complication occurring after cataract surgery. In order to prevent

endophthalmitis, several preoperative, perioperative, and postoperative measures were taken.

Moxifloxacin is a fourth - generation fluoroquinolone that affects gram-positive and gram-

negative bacteria. The study was conducted to evaluate the safety and efficacy of

intracameral moxifloxacin immediately after cataract surgery to prevent the risk of

endophthalmitis. A total of 65 patients were selected for the study. All the selected patients

had undergone a care cataract surgery and were retrospectively examined. Immediately after

the cataract surgery, intracameral moxifloxacin was instilled in some patients (moxifloxacin

group), but not in some other patients which is called as the control group. After cataract

surgery, the patients were examined at different time periods and the pre- and postoperative

findings were then compared. Adverse events were observed in both the groups and are

considered to be insignificant. Corneal edema was observed in 2 (6% ) subjects in the

moxifloxacin group (2 mild cases) and in 3 (9% ) subjects in the control group (2 mild cases,

1 moderate case). Anterior chamber cells ( 1 + ) were observed in 4 ( 12% ) subjects in the

moxifloxacin group and in 3 ( 9% ) subjects in the control group. These slight differences in


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corneal edema (P= 0. 623) and anterior chamber cell ( P = 0. 726) were not statistically

significant. Moxifloxacin were found to have an acceptable retinal safety profile. Therefore

the application of intracameral moxifloxacin for prophylaxis of endophthalmitis following

cataract surgery is both safe and effective.

4) Penetration of 0.3% ciprofloxacin, 0.3% ofloxacin, and 0.5% moxifloxacin into the

cornea and aqueous humor of enucleated human eyes

Eyes retrieved for corneal transplantation have a high rate of bacterial contamination that can

lead to graft infections. Therefore it is essential for eye banks to minimize bacterial

contamination. Ciprofloxacin, ofloxacin, and moxifloxacin were different antibacterial

agents used for the treatment of bacterial contamination. The study was conducted to quantify

the penetration of ciprofloxacin, ofloxacin, and moxifloxacin into the cornea and aqueous

humor of cadaver eyes. A total of 60 enucleated eyes, not eligible for corneal transplantation

were selected for the study. All the subjects were divided into three groups and immersed in

commercial solutions of 0.3% ciprofloxacin, 0.3% ofloxacin, or 0.5% moxifloxacin for 10

min. Only 1 eye of each donor was used. Whole corneas and samples of aqueous humor were

then harvested and frozen, and drug concentrations analyzed by liquid chromatography

tandem mass spectrometry. The mean corneal concentration of moxifloxacin was found to be

twice as high as ofloxacin, which was twice as high as ciprofloxacin. Moxifloxacin displayed

a mean concentration four times higher than the other antibiotics in the aqueous humor. If

these measurements would hold true in vivo, there will be a decreasing order of bactericidal

efficacy for antibiotics in the cornea should be moxifloxacin, ofloxacin, and ciprofloxacin. In

the aqueous humor, it should be moxifloxacin, ciprofloxacin, and ofloxacin. In either

medium, moxifloxacin should be far more efficient than ciprofloxacin and ofloxacin. The

amount of drug that penetrated the anterior chamber after a 10-min soaking was far below the

safe limit of endothelial toxicity of each preparation (21–23). Therefore, the application of

anti-bacterial drugs are found to be safe and effective especially moxifloxacin.

5) Intraocular penetration of sequentially instilled topical moxifloxacin, gatifloxacin,

and levofloxacin

Fluoroquinolones have been used extensively due to their excellent activity against ocular

pathogens, including both Gram-positive and Gram negative bacteria. The objective of study

was to compare the penetration levels of new fluoroquinolones, including the fourth-

generation fluoroquinolones (moxifloxacin and gatifloxacin) and a third-generation


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fluoroquinolone (levofloxacin) in the cornea, aqueous humor, and conjunctiva after topical

instillation in White rabbits. The rabbits were randomly divided into four treatment groups

for the study and one drop of each topical preparation was instilled in both eyes of each

animal at two-minute intervals. Instillation was repeated every 15 minutes for a total of three

drops of each fluoroquinolone per eye. Sixty (60) minutes after the final instillation, corneal,

aqueous humor, and conjunctival samples of rabbits were collected from each eye. The

sample concentrations of each fluoroquinolone were simultaneously determined by high-

performance liquid chromatography (HPLC). The mean concentration of moxifloxacin was

significantly higher than levofloxacin or gatifloxacin in the cornea (P = 0.0102 and P =

0.0006, respectively), aqueous humor (P = 0.0015 and P < 0.0001, respectively), and

conjunctiva (P = 0.0191 and P = 0.0236) respectively.

6) The efficacy of moxifloxacin in patients with bacterial keratitis

Keratitis is a sociomedical problem of moderately developed countries which in the loss of

vision. The aim of the study was to analyze the efficiency of moxifloxacin in the treatment of

bacterial keratitis. Keratitis is an acute or chronic inflammation of the cornea. Moxifloxacin

is an antibacterial agent that can be used for the local treatment of bacterial keratitis and/or

conjunctivitis. It has an excellent penetration through the cornea and conjunctiva and destroys

pathogens quickly. Moxifloxacin is a highly efficient anti-bacterial drug with low adverse

effects. The study was designed as a prospective, randomized, double-blind, clinical study.

The study included 30 patients with diagnosed keratitis. All the subjects were locally applied

with antibiotic moxifloxacin. 60 patients were placed in control group, with locally applied

artificial tears. After the application of therapies, all participants were subjected to complete

clinical ophthalmologic analysis for a period of 1–15 days. There was a statistically

significant difference between the study group patients who received moxifloxacin and the

control group patients who received arteficial tears. Moxifloxacin had significant therapeutic

effect (total benefit) both in terms of the effective shortening, time of healing (epithelization

corneal defects real fast) and reduction of complications of bacterial keratitis, without

unwanted effects.

7) Kinetics of kill of bacterial conjunctivitis isolates with moxifloxacin, a

fluoroquinolone, compared with the aminoglycosides tobramycin and gentamicin

Conjunctivitis is a common disease caused by many ocular pathogens, but is mainly bacterial

or viral in origin. Bacterial conjunctivitis is particularly common in children, with


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Streptococcus pneumoniae and Haemophilus influenzae being the most common causative

organisms. The purpose of study was to compare the time required in vitro for tobramycin

and gentamicin (aminoglycosides) and moxifloxacin (fourth-generation fluoroquinolone) to

kill S. pneumoniae and H. influenza. Bacterial conjunctivitis isolates of S. pneumoniae and

H. influenza were exposed to 1:1000 dilutions of moxifloxacin 0.5%, tobramycin 0.3%,

gentamicin 0.3%, and water (control). At different time periods, aliquots were collected, cells

were cultured, and viable cell counts were determined using standard microbiological

methods. Kinetics of kill studies with moxifloxacin ophthalmic solution 0.5% support a

greater speed of kill against S. pneumonia and H. influenzae than with the aminoglycosides,

tobramycin ophthalmic solution 0.3% and gentamicin ophthalmic solution 0.3%.

Moxifloxacin can be used as a first-line treatment for bacterial conjunctivitis to minimize

patient symptoms and to limit the contagiousness of the disease.

8) Concentrations of besifloxacin, gatifloxacin and moxifloxacin in human conjunctiva

after topical ocular administration

Bacterial conjunctivitis is normally an acute, self-limiting infection caused by Gram-positive

species and the Gram-negative species. Bacterial conjunctivitis are usually treated with

topical antibiotics for the speed recovery from signs and symptoms associated with the

infection. The study was conducted to evaluate the pharmacokinetic profiles of 3

fluoroquinolones in the conjunctiva of healthy adults. One-hundred eight (108) subjects of at

least 18 years of age without any ocular abnormalities were selected for the study. All

subjects received one drop of besifloxacin (0.6% suspension), gatifloxacin (0.3% solution), or

moxifloxacin (0.5% solution) ophthalmic formulations in one eye prior to conjunctival

biopsy. Samples were collected from all subjects at different time periods (15 minutes, 30

minutes, 2 hours, 6 hours, 12 hours, or 24 hours) after dosing. The maximum mean

concentration (Cmax) occurred at 15 minutes for all three compounds. . The Cmax for

moxifloxacin (10.7 µg/g) was more than double that of gatifloxacin (4.03 µg/g) and

besifloxacin (2.30 µg/g). Concentrations decreased with each subsequent time point.

Besifloxacin had the greatest mean residence time (4.7 hours) in the conjunctival tissue. No

serious adverse effects were occurred in this study. The most commonly reported adverse

events were ocular pain and headache. The three medications provide broad-spectrum

coverage and cause few adverse reactions. They offer excellent therapeutic choices for

treating bacterial conjunctivitis.


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9)Antibacterial efficacy of prophylactic besifloxacin 0.6% and moxifloxacin 0.5% in

patients undergoing cataract surgery

Bacterial endophthalmitis is a vision-threatening complication after cataract surgery. The

most common causes of bacterial endophthalmitis are gram positive organisms. Besifloxacin

is an ophthalmic drug with antibacterial properties. The purpose of this study was to

investigate the ocular bacterial flora in patients who had undergone cataract surgery and to

compare the antibacterial effects of besifloxacin ophthalmic suspension 0.6% and

moxifloxacin ophthalmic solution 0.5% in these patients. This was a prospective,

randomized, laboratory-masked clinical trial. All patients received besifloxacin or

moxifloxacin four times a day for 3 days before cataract surgery in the surgical eye and 1

hour before surgery in the nonsurgical fellow eye. Conjunctival and eyelid swabs were

obtained from both eyes and were processed for bacterial colony counts (in terms of colony-

forming units) and species identification. Fifty-nine patients were selected for the study.

Majority of the samples were found to be gram negative. Besifloxacin reduced the lid CFU

estimate 1 hour following instillation of a single drop (P=0.039) than moxifloxacin.

Besifloxacin was more active in vitro against MRSE. Besifloxacin appeared more effective in

reducing bacterial counts on eyelids of patients undergoing cataract surgery. There were no

adverse events, either ocular or nonocular, reported for any patient in either the besifloxacin

or moxifloxacin treatment groups.

10)Pharmacokinetics and aqueous humor penetration of levofloxacin 1.5% and

moxifloxacin 0.5% in patients undergoing cataract surgery

Microbial keratitis and endophthalmitis can present a substantial risk to vision.

Fluoroquinolone antimicrobial agents, like levofloxacin and moxifloxacin, have in vitro

activity against the bacterial pathogens that threaten the health of the eye. The study was

conducted to compare the pharmacokinetics in aqueous humor of levofloxacin 1.5% and

moxifloxacin 0.5% ophthalmic solutions of patients undergoing cataract surgery. This was a

two-visit, randomized, single-center, single-masked, active-comparator and parallel-group

study. Subjects who had underwent cataract surgery and met the requirements of PK analysis

were selected. Three days prior to cataract surgery, each patient instilled one drop of the

assigned study medication into the operative eye four times daily at different time periods.

Aqueous humor specimen was collected from the eye at the randomized time point and

assayed using liquid chromatography and tandem mass spectrometer. The obtained mean

concentrations were statistically significant at time periods. The mean concentration of


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levofloxacin was 50% higher than moxifloxacin concentrations across all time points. No

treatment-emergent adverse events were reported during the course of the study.

Levofloxacin 1.5% shows a greater potential for bacterial eradication.

Clinical Trials : Moxifloxacin

1)Pharmacokinetic Evaluation of Moxifloxacin in Aqueous Humor Samples Following

Preoperative Antibiotic/Steroid Dosing in Cataract Surgery Patients


The purpose of study was to determine the aqueous penetration of Moxifloxacin with

Vigadexa drug preoperatively in cataract patients. 36 subjects were selected for the clinical

trials. This was a phase – 4 clinical trial. The drug selected for the trial was Moxifloxacin

0.5% / Dexamethasone ophthalmic solution (Vigadexa). The health status of volunteers must

be acceptable before intervention. One drop of drug was installed in the study eye 2 days

before the surgery, followed by 1 drop instilled 4 times a day before the day of surgery. On

the day of surgery, 1 drop was instilled 60 minutes prior to the procedure. During the cataract

surgery, 0.15 millimetre sample of an aqueous humour was collected. The concentration of

moxifloxacin was measured using high performance liquid – spectroscopy. The Mean

Aqueous Humor Concentration of Moxifloxacin was found to be 1110.6. Among the 36

subjects, only 31 patients completed the trial. Majority of subjects were females. Only 2

patients were reported with mild adverse events. In fact adverse serious events were not

reported. Therefore Moxifloxacin was found to be safe and effective in cataract patients. This

clinical trial was conducted in Brazil from April 2012 – August 2012.

2) An Evaluation of the Safety and Efficacy of Moxifloxacin Ophthalmic Solution 0.5%

Versus Ofloxacin Ophthalmic Solution 0.3% in the Treatment of Bacterial

Conjunctivitis in Chinese Patients


Moxifloxacin and ofloxacin are drugs that can be used against bacterial infections. The study

was conducted to evaluate the efficacy of Moxifloxacin 0.5% relative to Ofloxacin 0.3% in

treatment of bacterial conjunctivitis in Chinese patients. This was a 3 – phase clinical trial.

The trial began from March 2012 to April 2014. The drug selected for the study was

Moxifloxacin 0.5% and Ofloxacin 0.3%. 985 patients were selected for this study. Patients

diagnosed with bacterial conjunctivitis were enrolled for the trials. From the 985 enrolled, 3

participants were exited as screen failures prior to randomization. Majority of the subjects


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were females. Subjects will self-administer 1 drop of study drug into the operative eye 3

times per day (TID) in each eye for 7 days with a test-of-cure (TOC) at Day 9. 489 patients

were instilled with Moxifloxacin 0.5% and only 469 patients completed the experiment. On

the other hand, 493 patients were instilled with Ofloxacin 0.3% and only 469 patients

completed the trials. The investigator rated the ocular signs of bacterial conjunctivitis on a 4 –

point scale, with 0 = normal/absent ; 1 = mild ; 2 = moderate and 3 = severe . The result of

the clinical cure rate is presented as the percentage of participants for which the sum of the

numerical scores for the 2 cardinal ocular signs of bacterial conjunctivitis was 0 at day 9 Toc

/ Exit visit. The result obtained was 85.4% for Moxifloxacin and 81.4% for Ofloxacin.

Microbiological specimen(s) from the affected eye(s) were collected accordingly to protocol

– defined process. Microbiological success rate is presented as the percentage of participants

for which the pre – therapy pathogens at Visit 1 (Day 1) were eradicated at Day 9 Toc / Exit

visit. The percentage obtained was 95.3% for Moxifloxacin and 94.8% for Ofloxacin. Some

patients were reported with mild adverse events.

3)Aqueous Absorption and Pharmacokinetics of Besivance Versus VIGAMOX in

Patients Undergoing Phacoemulsification


The objective of this study is to compare drug concentrations in aqueous humor following

ocular instillation of Besivance or VIGAMOX in subjects undergoing cataract surgery. This

was a phase 3 clinical trial. The drug used for the study was Moxifloxacin and besifloxacin.

120 healthy adults were selected for the study. Eligible subjects will be randomized to

treatment with Besivance or VIGAMOX. Subjects will self-administer 1 drop of study drug

into the operative eye 4 times a day for 3 days prior to surgery. Subjects will have one final

drop of study medication on the day of surgery. Prior to the cataract surgery, a sample of

aqueous humor will be collected by paracentesis. Concentration of Besivance and

VIGAMOX in the aqueous humor will be measured using standardized high pressure liquid

chromatography and mass spectrometry assays. Pharmacokinetic parameters determined from

the aqueous humor concentration will minimally include the area under the curve and the

maximum concentration. 60 subjects were instilled with VIGAMOX and 57 subjects

completed the trials. On the other hand, 60 subjects were instilled with Besivance and 59

subjects completed the trials. The calculated mean value for Besivance and VIGAMOX is

56.4525 and 443.07 respectively. Adverse events were not reported during the study.

Aqueous absorption of Besivance is greater than VIGAMOX because of unique properties of


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Besivance which promote increased contact time of this antibiotic with the ocular surface.

The study was conducted in US from May 2011to January 2013.

4) Assessment of the Concentrations of Besifloxacin, Moxifloxacin, or Gatifloxacin in

the Aqueous Humor of Subjects


The purpose of this study is to assess the concentration of besifloxacin, moxifloxacin, or

gatifloxacin in aqueous humor samples collected following topical instillation of the

associated formulation in subjects undergoing cataract surgery. This was a phase 1 clinical

trial. The drug used for the study was Moxifloxacin ophthalmic solution 0.5% (Vigamox),

Besifloxacin and Gatifloxacin ophthalmic solution 0.3% (Zymar). The trial began from

February 2009 to August 2009. 36 subjects were selected for the clinical trials. Subjects will

instill the study medication in the study eye prior to making an incision for cataract extraction

surgery. An aqueous humor specimen was collected from the study eye for determination of

drug concentration 60 min after study drug instillation. They were obtained by calculating

the Aqueous Humor Drug Concentration. The concentration of Moxifloxacin, Besifloxacin

and Gatifloxacin was 0.1349 (0.5820), 0.6681(0.4980) and 0.1251 (0.07624) respectively.

Adverse events were not reported during the study. The study was conducted in US.

5) Study of AzaSite (Azithromycin) Versus Vigamox in the Conjunctiva of Healthy

Volunteers


The study was conducted to evaluate the drug concentrations of AzaSite™ compared to

Vigamox at various time points in conjunctiva tissue of healthy volunteers. This was a phase

4 clinical trial. The drug used for the study was Moxifloxacin and Azithromycin eyedrops.

Moxifloxacin and Azithromycin were used against bacterial infections and eye infections

respectively. 48 healthy participants were selected for the clinical trials. Subjects will instill

the study medication in the study eye as a single drop in a single eye. 48 healthy participants

were divided into 8 different groups of 6 members each. The study medications were instilled

to 8 groups at different time periods (30 min, 2 hours, 12 hours and 24 hours post dose).

Majority of subjects were females. The were obtained by calculating the Conjunctiva

Concentration of Azithromycin and Moxifloxacin. The concentration of Moxifloxacin and

Azithromycin at different time periods (30 min, 2 hours, 12 hours and 24 hours post dose)


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were 1.9 (2.0), 3.8 (9.0), 0.0 (0.0), 0.0 (0.0) and 130.8 (89.1),51.6 (26.0), 67.1 (51.8), 31.9

(20.4) respectively. Some patients were reported with mild adverse events.

Therapeutic Application of Moxi-dexamethasone

1) Efficacy and Tolerability of a Combined Moxifloxacin/Dexamethasone Formulation

for Topical Prophylaxis in Phacoemulsification: An Open-Label

Cataract surgery with intraocular lens (IOL) implantation is the most common ophthalmic

surgical operation. The 0.05 to 0.14% of cataract patients suffer from postoperative

endophthalmitis (POE). Normally ophthalmologists apply topical antibiotic drops to prevent

this. A fixed-combination eye preparation not only helps in cutting costs but also improves

patient compliance due to convenience in dosing and application. The combination

formulation of moxifloxacin 0.5%/dexamethasone 0.1%(vigadexa) is used. Its efficiency and

tolerability in the prevention of postoperative inflammation and infection in predominantly

Asian Patients is studied. With 64 patients 15-day, open-label, and single-arm clinical trial

was conducted at the American Eye Center, Philippines. Adult patients (≥18 years) with a

diagnosis of cataract underwent clear cornea incision phacoemulsification with IOL

implantation. Surgery was performed in only one eye in each patient.no other antimicrobial

drugs should not be taken by the patients. Patients were instructed to instill one drop from a

labeled bottle of moxifloxacin 0.5%/dexamethasone 0.1% (Vigadexa) 4 times a day in the

conjunctival sac of the eye to be operated on beginning from day −1 (1 day before the

surgery) until day 15 (15 days after the surgery).The patients underwent phacoemulsification.

During the screening visit (within 14 days prior to surgery), baseline values of both eyes were

recorded for best-corrected visual acuity (BCVA), and intraocular pressure (IOP) was

measured. Patients were examined for the presence of anterior chamber (AC) cells. Patients

were seen postoperatively on days 1, 3, 8, and 15. At each visit, patients were examined for

signs of infection, inflammation, and ocular pain. An increased inflammatory response was

observed for the first few days after surgery which gradually declined until day 15. The

combination moxifloxacin 0.5%/dexamethasone 1% was as effective in preventing infection

and controlling inflammation postoperatively compared to when its individual components

were administered concurrently. patients did not report any discomfort during or immediately

after its application.


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2) Simultaneous Determination of Moxifloxacin Hydrochloride and Dexamethasone

Sodium Phosphate in Eye Drops by HPLC and Absorbance Correction Method

HPLC , HPTLC, LC-MS , Capillary electrophoresis and UV Spectroscopy method has been

reported for determination of moxifloxacin hydrochloride and dexamethasone sodium

phosphate alone or in combination with other drugs in pharmaceutical formulations and in

human plasma. The aim of this work is to determine both drugs simultaneously by simple,

rapid, and selective HPLC and absorbance correction method which could be used for quality

control and routine analysis. All absorption spectra were recorded with a Shimadzu UV-1700

Pharmaspec, UV-Visible double-beam spectrophotometer with 1 cm quartz cuvettes. The

spectral bandwidth was 0.2 nm. HPLC instrument was equipped with a model series LC-10

AS pump. A Grace smart reversed-phase C18 column was used as the stationary phase. Class

CR10 software was used for data acquisition.Milflox-DM eye drops and Occumox-DM eye

drops were used for analysis. Each eye drops claimed to contain 0.5 % w/v MOXI and 0.1%

w/v DEXP.Calibration graphs for both MOXI and DEXP were obtained by plotting the peak

area against concentration, and the corresponding regression equations were calculated by

HPLC. In absorbance correction method the difference in absorbance between 244.2 nm and

357 nm is due to DEXP and this difference was plotted against DEXP concentration. The

absorbance at 357 nm is due to MOXI only and was plotted against MOXI concentration. The

linearity of the HPLC and absorbance correction methods for the determination of MOXI and

DEXP was evaluated by analyzing a series of different concentrations of each drug. The

developed HPLC and Absorbance correction methods are precise, specific, and accurate.

Statistical analysis proves that the methods are suitable for the analysis of MOXI and DEXP

as a bulk drug and in pharmaceutical formulation without any interference from the

excipients.

Simultaneous determination of dexamethasone and moxifloxacin in pharmaceutical

formulations using stability indicating HPLC method

Moxifloxacin hydrochloride and dexamethasone have been analysed by various techniques

either alone or in combination with other drugs. Attempts were made to develop and validate

simple, precise, and sensitive, isocratic reverse phase stability indicating high performance

liquid chromatographic method for the simultaneous determination of moxifloxacin

hydrochloride and dexamethasone and their stress induced degradation products in

pharmaceutical formulations. Occumox DM and Moxiblu-D eye drops (containing 5 mg per

ml of moxifloxacin and 1 mg per ml of dexamethasone) were used for method applications.


613


The HPLC system consisting of Shimadzu LC-20A system is equipped with model LC-20AT

pump,The mobile phase was consisting of methanol and 20 mM phosphate buffer. Flow rate

of the mobile phase was 1.5 mL min1 and all chromatographic experiments were performed

at room Temperature. Due to high carbon content and hydrophobic character of moxifloxacin

hydrochloride and dexamethasone these drugs can be separated through C8 or C18 stationary

phases. The variations in the composition of the mobile phase and dissimilar stationary

phases had substantial influences on peak shape, tailing factor, retention factor, theoretical

plates and resolution.Under the mentioned chromatographic conditions highly symmetrical

and sharp peaks of moxifloxacin hydrochloride and dexamethasone were obtained at

retention times of 3.372, and 6.503 min, respectively.The developed method was validated

by testing its linearity, accuracy, precision, specificity, limits of detection and quantitation. It

is also clear from the chromatograms that both the active ingredient peaks in all the stress

conditions were free from any sort of degradation impurities. All these convince us to

conclude that the method can be successfully used for any sort of stability and validation

studies.

Endophthalmitis following cataract surgery and intracameral antibiotic: Moxifloxacin

resistant Staphylococcus epidermidis

Endophthalmitis is a rare but potentially sight-devastating complication after cataract surgery,

estimated to affect between 0.012% and 0.2% of patients. A 76- year old female with a past

medical history of quiescent birdshot chorioretinitis (BSCR) and rheumatoid arthritis (RA)

was referred for cataract surgery, the patient underwent uneventful clear corneal

phacoemulsification with insertion of a posterior chamber intraocular lens (PCIOL) for the

right eye. Moxifloxacin was injected intracamerally at the end of the case. The patient

reported decreased vision and new onset floaters.Cultures of the vitreous aspirate grew

Staphylococcus epidermidis, resistant to moxifloxacin. The inflammation resolved over two

months. Eight months later, the patient underwent uncomplicated cataract surgery in the left

eye. Intracameral antibiotics were not used, however her systemic immunosuppressive

therapy was held for several weeks perioperatively. One year after the initial surgeries, the

patient had an uncorrected visual acuity of 20/20 in each eye. The use of IC moxifloxacin has

been reported to reduce the rate of acute-onset postoperative endophthalmitis in many series.

However, endophthalmitis may still occur with its use. Adequate concentrations of IC

antibiotics need to be achieved in order to exceed MIC values of the targeted pathogen. Other


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preventive methods (such as strict aseptic measures) remain important in reducing the

incidence of this devasting complication.

Latrogenic Cushing’s Syndrome Following Short-Term Intranasal Steroid Use

Development of iatrogenic Cushing‟s syndrome (CS) due to oral steroid use is common.

Some features of CS like increased intraocular pressure, cataract, benign intracranial

hypertension, aseptic necrosis of the femoral head, osteoporosis, and pancreatitis are more

frequently observed after exogenous steroid exposure. CS following use of ocular

administration of steroids (eye drops) has not been reported. A 6-year-old girl was referred to

our endocrinology clinic for evaluation. Her height was 102 cm, weight 18kg, and body mass

index was 17.3kg/m2 found that the child was prescribed combined moxifloxacin-

dexamethasone eye drops (Milflox-DM eye drops, Unimed, India) by her family physician, to

be applied intranasally for epistaxis. She has finished 6 bottles in 3 months. The steroid drop

administration was stopped; hydrocortisone was started in a dose of 15mg/day. When the

patient was evaluated 1 month after the initial diagnosis, it was observed that a significant

decrease in the facial puffiness had occurred. Her use of 2 bottles per month is equivalent to

20 mg of dexamethasone per month which is around 0.7mg of dexamethasone per day, which

is high for a 6-year-old girl. Moxifloxacin does not inhibit or stimulate the hepatic

microsomal P450 system and hence has no effect on steroid metabolism. Since drops were

used instead of nasal spray, it is likely that a significant amount would be swallowed and

absorbed from the gastrointestinal tract, resulting in CS. The purpose of this research article

was to highlight the occurrence of CS even with steroid eye drop preparations, some of which

can contain high concentrations of steroids. Steroids with a high potency, such as

dexamethasone, increase the risk of developing CS.

Efficacy and tolerability of a combined moxifloxacin/dexamethasone formulation for

topical prophylaxis and reduction of inflammation in phacoemulsification: a

comparative, double masked clinical trial

The incidence of acute postoperative endophthalmitis among cataract patients in the

developed world ranges from 0.04% to 0.099%. Most surgeons prescribe topical antibiotics

immediately following surgery and for the next 10–14 days, when microbial colonization is

most likely to occur.

The scientist evaluated the clinical usefulness of a new single-vehicle, fixed-dose

combination antibiotic/ corticosteroid formulation, Vigadexa*, consisting of 0.5%


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moxifloxacin (Vigamox*) and 0.1% dexamethasone (Maxidex*). Phacoemulsification and

intraocular lens (IOL) implantation was performed in 139 patients with cataracts. Each

patient had surgery in only one eye. The first group comprised 64 eyes that received the

combination moxifloxacin/dexamethasone eye drops and a dextran/ methylcellulose placebo

(Lacrima Plus†). The second group comprised 62 eyes that were treated with 0.5%

moxifloxacin and 0.1% dexamethasone eye drops in the conventional manner. Patients were

asked to subjectively rank their eye pain on a five-point scale, from 0 = none to 5 = severe.

Any sign of active ocular inflammation – redness, edema, tearing, or discharge – was

documented, and slit-lamp examination produced information regarding structural changes in

the cornea and conjunctiva. A Goldmann applanation tonometer was used to measure the

intraocular pressure. Physicians rated bacterial infection to be absent in both groups on days

1, 3, 8, and 15. The efficacy of the study medication was assessed by comparing the two

treatment groups for signs of Inflammation, including hyperemia or edema of the lids or

conjunctiva, ocular discharge, structural changes of the cornea, photophobia, and excessive

tearing. With regard to the safety parameters of visual acuity, ocular pain, and intraocular

pressure, eyes that received the combined moxifloxacin/dexamethasone eye drops had

virtually identical to those dosed conventionally with moxifloxacin and dexamethasone from

separate bottles. scientist believe that cataract patients will find the single-vehicle, fixed-dose

moxifloxacin/dexamethasone eye drops easier to use and will enjoy the benefits of single-

bottle drop application.In this study population of cataract patients, the single vehicle, fixed-

dose combination of 0.5% moxifloxacin and 0.1% dexamethasone eye drops was found to be

as well tolerated as, and therapeutically equivalent to, conventional, separate dosing with

0.5% moxifloxacin and 0.1% dexamethasone.

7)Efficacy and tolerability of a fixed-dose moxifloxacin – dexamethasone formulation

for topical prophylaxis in LASIK: a comparative, double-masked clinical trial

Laser-assisted in situ keratomileusis (LASIK) is the most popular operation for refractive

correction. LASIK patients are usually prescribed antibiotic and steroid eye drops for the first

5–14 days after surgery to prevent infection and minimize inflammation, Alcon Laboratories,

Inc. has developed a new antibiotic–steroid formulation consisting of 0.5% moxifloxacin and

0.1% dexamethasone (MFLX/DEX). A total of 64 consecutive patients who presented for

LASIK correction were randomly assigned to receive either the fixed-dose combination of

MFLX/DEX formulation or the separate bottles of moxifloxacin and dexamethasone. Patients

who were receiving a topical prostaglandin for IOP control were instructed to discontinue its


616


use at least 4 days prior to surgery and until the study was completed. All surgical candidates

were told to stop wearing contact lenses for at least 2 weeks before the LASIK procedure.All

patients were instructed to apply 1 drop from each bottle in both eyes 4 times a day. Two

days before surgery the baseline values were recorded for visual acuity (VA), IOP, number of

cells in the anterior chamber, clinical impression of inflammation of eyelids and conjunctiva,

ocular pain, burning or itching sensation, and fundus status. These assessments were repeated

on the fi rst day after surgery (Day 1) and thereafter on days 3, 8, and 15. With regard to eye

pain, no statistically significant differences were observed between the MFLX/DEX

combined and the moxifloxacin and dexamethasone separate groups. The present study

evaluated a fixed-dose combination product of moxifloxacin and dexamethasone in patients

undergoing LASIK. From an economical standpoint, the combination product reduces

medication cost since patients only need to purchase a single bottle of medication instead of

two separate bottles. A fixed-dose formulation of moxifloxacin and dexamethasone was

found to be safe and effective in preventing infection and controlling inflammation post-

LASIK

8)Management of traumatic proptosis in a pug: A case study

Proptosis is forward displacement of globe which occur secondary to any blunt trauma to

head . Proptosis typically occurs in dogs following trauma to the face or head. During trauma,

the globe is luxated from the orbit, and eyelid spasms prevent its retraction. Secondary orbital

hemorrhage and swelling displace the globe further from the orbit following corneo-

conjunctival drying and malacia. Only 20-40% of dogs that have the reattachment of the

eyeball regain their vision. A three year old male pug of 10 kg weight was presented with

unilateral traumatic proptosis having recent history of blunt head trauma by hitting head

against the wall .Clinical examination revealed partial prolapse of right eye globe through the

pulpebral fissure with severe periorbital edema, haemorrhage without fracture of skull. Early

presentation for early treatment reduce inflammation and edema. Treatments of proptosis

depend upon the type, duration of trauma and damage to globe. Treatment was started using

triflupromazine at 4mg/kg body weight. The protruded eye ball was cleaned with sterile pads

soaked in normal saline to remove dirt and debrise, followed by intrapalpebral injection of

gentamicine and dexamethasone. Pug was given eye drop of moxifloxacine and

dexamethasone 4times a day for instillation. Animal recovered successfully after 7days of

regular treatment. Therapeutic management was successful with high prognosis for proptosed


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globe. Vision was normal in treated pug as assessed after 15 days of recovery by simple

vision testing using junction box.

9)Safety and Efficacy of Moxifloxacin-Dexamethasone Eyedrops as Treatment for

Bacterial Ocular Infection Associated with Bacterial Blepharitis

Fourth generation fluoroquinolones have a broad spectrum of activity against Gram-positive

bacteria, and are considered appropriate choices for treating an ocular infection caused by an

unknown organism with unknown resistance. A single preparation combining moxifloxacin

plus dexamethasone could reduce treatment burden and improve patient compliance relative

to the independent dosing of an antibiotic and steroid for the treatment of blepharitis. The

purpose of this study was to evaluate the efficacy and safety of a fixed combination of

moxifloxacin 0.5%/dexamethasone 0.1% eye drops in the treatment of bacterial ocular

inflammation and infection (blepharitis) compared with the concomitant administration of

moxifloxacin 0.5% and dexamethasone, 0.1% eye drops from individual bottles. Subjects 18

years and older diagnosed with bacterial blepharitis were recruited from the Ophthalmology

Department from Brazil. The fixed-dose group received a fixed combination of moxifloxacin

0.5%/ dexamethasone 0.1% ophthalmic solution the concomitant group received

moxifloxacin 0.5% ophthalmic solution (bottle A) and dexamethasone 0.1% ophthalmic

solution (bottle B).Intraocular pressure (IOP) was measured in both eyes with a Goldmann

applanation tonometer. A specimen for microbiological analysis was collected using a sterile

disposable collection and transportation system from the affected eye Samples were cultured

onto 5% blood (sheep) agar and chocolate agar as well as into tryptic soy broth (TSB) for 48

hours. All eyes had blepharitis. The treatment groups had similar demographics and baseline

characteristics. This clinical study evaluated the efficacy and safety of a fixed combination of

moxifloxacin 0.5%/dexamethasone 0.1% eye drops in the treatment of bacterial ocular

inflammation and infection compared with concomitant administration of moxifloxacin 0.5%

and dexamethasone, 0.1% eye drops from individual bottles. The fixed-combination

treatment was as effective clinically as moxifloxacin, 0.5% and dexamethasone, 0.1% used

concomitantly in treatment of ocular infection and inflammation associated with bacterial

blepharitis.

This clinical trial was to demonstrate that the combination formulation of

Moxifloxacin/Dexamethasone Eye Drop is effective and safe for the prevention of

postoperative inflammation as a consequence of cataract extraction surgery. This was a phase


618


4 trial. The drug used was Vigadexa (moxifloxacin 0.5% and dexamethasone 0.1%) eye

drops. 64 patients were selected from September 2008 to February 2009 but only 60 of them

completed the trial. Vigadexa was instructed to apply one drop for 6 hours. All patients were

adults. 43 patients were above 64 age group. 37 patients were female and the rest were males.

Anterior chamber inflammation was evaluated based on the number of cells per high-power

field measured using the narrowest slit beam of the lamp (0.5 at a height of 8mm). Anterior

chamber cells was recorded on a 0-4 point scale,0 = Less than 5 cells; 1 = Mild: 5-10 cells; 2

= Moderate:11-20 cells; 3 = Marked: 21-50 cells; 4 = Severe: Greater than 50 cells /

hypopyon. 91.7% patients anterior chamber inflammation rate was scale 0. After surgery for

15 days no ocular pain was observed in 96.7% patients. Serious adverse event wasn‟t

observed in any of the patients. This clinical trial was conducted in America

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Phacoemulsification: An Open-Label Single-Arm Clinical Trial. J. Ophthalmol, 2011;

2011.

22. Kwatra, B. A REVIEW ON POTENTIAL PROPERTIES AND THERAPEUTIC

APPLICATIONS OF GRAPE SEED EXTRACT. World J. Pharm. Res, 2020; 9: 2519–

2540.


APPLICATIONS OF BRANCHED CHAIN AMINO. WORLD J. Pharm. Pharm. Sci,

2020; 9: 561–588.

24. Kwatra, B. & Arora, C. The Studying Of Movements Resonant the Pendulum Elastic.

Indian J. Appl. Res, 2020; 10: 1–2.

25. Kwatra, B. COLLAGEN SUPPLEMENTATION: THERAPY FOR SKIN DISORDERS :

A REVIEW. World J. Pharm. Res, 2020; 9: 2504–2518.


APPLICATIONS OF LYCOPENE. Int. J. Med. Biomed. Stud, 2020; 4: 33–44.

27. Kwatra, B. & Mudgil, M. LIGHT ASSISTED TIO2-BASED NANOCOMPOSITE

SYSTEMS: A NOVEL TREATMENT FOR CANCER. Int. J. Med. Biomed. Stud, 2020;

4: 28–32.

28. Kwatra, B. A Review on Potential Properties and Therapeutic Applications of Vitamin D.

Int. J. Sci. Res, 2020; 9: 682–691.

29. Kwatra, B. HYDROQUINONE: A novel growth inhibitor and apoptosis inducer in U-251

MG CELLS. Int. J. Med. Biomed. Stud, 2019; 3: 15–16.

30. Kwatra, B. HACKING THE BLOOD-BRAIN BARRIER. Eur. J. Biol. Med. Sci. Res,

2017; 5: 10–13.

31. Kwatra, B. EXPRESSION AND CHARACTERIZATION IN PICHIA PASTORIS BY

CLONING OF DELTA 4 DESATURASE FROM ISOCHRYSIS GALBANA. Indian J.

Appl. Res, 2019; 9: 1–2.

32. Kwatra, B. CALCIUM AND IRON ABSORPTION: INVITRO STUDIES. Int. J. Med.

Biomed. Stud, 2019; 3: 59–61.

33. Kwatra, B. Allicin-An After Digestion Antimicrobial Agent. ACTA Sci. Microbiol, 2019;

2: 48–51.

34. Kwatra, B. LOCATOR THEORY FOR ELE-MENTS IN PERIODIC TABLE „LEPT‟.


621


Glob. J. Pure Appl. Chem. Res, 2017; 5: 9–10.

35. Kwatra, B. & A, A. UTERINE CANCER: SEX DOMINANT CHARACTER. Int. J. Adv.

Res, 2020; 08: 663–667.

36. Kwatra, B. Studies on People Employed in High Risk Workplace : Between Genetic

Polymorphism for Tumor Necrosis Factor ( TNF- Α ) and Blood Pressure. Int. J. Innov.

Res. Technol, 2020; 6: 268–270.

37. Kwatra, B. & Arora, C. Investigation of Conductance Quantization with Magnetic Field

Control and Application of Biosensor. Int. J. Innov. Res. Technol, 2020; 6: 271–272.

38. Kwatra, B. Candidate genes of OCD interacts with human retrovirus to form new link in

inflammatory hypothesis. Int. J. Sci. Appl. Res, 2020; 7: 1–2.

39. Kwatra, B. COLLAGEN SUPPLEMENTATION: THERAPY FOR THE PREVENTION

AND TREATMENT OF OSTEOPOROSIS AND OSTEOARTHRITIS : A REVIEW.

WORLD J. Pharm. Pharm. Sci, 2020; 9: 589–604.

40. Kwatra, B. & Arora, C. THE UNEXPLAINED SIMILARITY BETWEEN THE

ATOMIC AND GRAVITATIONAL MODELS. Int. J. Adv. Res, 2020; 8: 1099–1107.

41. Kwatra, B. A Review on Potential Properties and Therapeutic Applications of DHA and

EPA. ijppr.humanjournals, 2019; 16: 140–176.

42. Kwatra, B. Tinospora Crispa As A Future Cure For Obesity/Cholesterol. Int. J. Sci.

Technol. Res, 2017; 6: 340–341.

43. Bharat Kwatra. Procuring Natural Dye for Solar Cell Using Leaf Waste. Int. J. Sci. Eng.

Res, 2019; 7: 46–47.

44. Kwatra, B. THE SIMVASTATIN AND DMXAA ON THE CO-CULTURE OF B16.F10

MELANOMA CELLS AND MACROPHAGES SHOWS ANTITUMOR ACTIVITY.

World J. Pharm. Res, 2019; 8: 1318–1319.

45. Kwatra, B. Bioactive-Compounds: alternative to control Candida spp. Int. J. Sci. Res.

Rev, 2019; 8: 221–223.

46. Kwatra, B. Effects of Mineral Separation by Time and Enteric Coating Mechanism for

Calcium and Iron Absorption in Mammalia. Int. J. Sci. Res, 2019; 8: 1265–1270.

47. Kwatra, B. Maprovit 3, 6, 9: Perfect Companion of your Immune System to Fight Corona

Virus Hit. Int. J. Sci. Res, 2020; 9: 241–241.

48. Kwatra, B. & Mudgil, M. Untangling the Mathematical Relation Between Natural

Selection and Adaptive Radiation Using Macromolecules and Microevolutionary Forces.

Int. J. Sci. Res. Sci. Technol. IJSRST |, 2020; 7: 313–339.

49. Chaitanya Arora1, B. K. Mathematical and Statistical Approach to Define Past Present


622


Future Events. Int. J. Sci. Res, 2019; 8: 261–263.

50. Kwatra, B. MECHANISMS OF PATTERN FORMATION OF FBP17 IN MAST

CELLS. Int. J. Adv. Res, 2019; 7: 413–414.

51. Mudgil1, M. & Kwatra2, B. Mosquito Menace Aim: Observing the life cycle of Aedes

aegypti mosquito and understanding its behavior towards different natural oils for

encouraging natural methods of repellence. Int. J. Sci. Res, 2019; 8: 1314–1315.


APPLICATIONS OF BROMELAIN. www.wjpps.com, 2019; 8: 488–500.

53. Kwatra, B. Holothuroidea (Sea Cucumber): Key to Anti-Aging. Int. J. Sci. Res, 2019; 8:

884–884.

54. Kwatra, B. & Mudgil, M. PROTONATED CRAB SHELL WASTE AS FUNGAL

INHIBITOR. Int. J. Med. Biomed. Stud, 2019; 3: 111–116.

55. Bucci, F. A., Nguimfack, I. T. & Fluet, A. T. Pharmacokinetics and aqueous humor

penetration of levofloxacin 1.5% and moxifloxacin 0.5% in patients undergoing cataract

surgery. Clin. Ophthalmol, 2016; 10.

56. Wagner, R. S. et al. Kinetics of kill of bacterial conjunctivitis isolates with moxifloxacin,

a fluoroquinolone, compared with the aminoglycosides tobramycin and gentamicin. Clin.

Ophthalmol, 2010; 4.

57. Bucci, F. A. et al. Antibacterial efficacy of prophylactic besifloxacin 0.6% and

moxifloxacin 0.5% in patients undergoing cataract surgery. Clin. Ophthalmol, 2015; 9.

58. Cetinkaya, S., Cetinkaya, Y. F., Acir, N. O. & Dadaci, Z. Application of intracameral

moxifloxacin to prevent endophthalmitis in cataract surgery. Int. Eye Sci, 2015; 15.

59. Sugioka, K. et al. Intraocular penetration of sequentially instilled topical moxifloxacin,

gatifloxacin, and levofloxacin. Clin. Ophthalmol, 2009; 3.

60. Torkildsen, G., Proksch, J. W., Shapiro, A., Lynch, S. K. & Comstock, T. L.

Concentrations of besifloxacin, gatifloxacin, and moxifloxacin in human conjunctiva after

topical ocular administration. Clin. Ophthalmol, 2010; 4.

61. Silva, G. C. M., Jabor, V. A. P., Bonato, P. S., Martinez, E. Z. & Faria-e-Sousa, S. J.

Penetration of 0.3% ciprofloxacin, 0.3% ofloxacin, and 0.5% moxifloxacin into the

cornea and aqueous humor of enucleated human eyes. Brazilian J. Med. Biol. Res, 2017;

50.

62. Janicijevic, K. et al. The efficacy of moxifloxacin in patients with bacterial keratitis.

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THERAPEUTIC APPLICATION BROMFENAC ......2Shandong University Cheeloo College of Medicine, Jinan, China. 3St Teresa's College Ernakulam, M G University, Kerala, India. *Project Mentored