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In This Article
 »  Abstract
 » Introduction
 »  Materials and Me...
 » Calibration
 » Results
 » Discussion
 » Acknowledgments
 »  References
 »  Article Figures
 »  Article Tables

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 Table of Contents    
RESEARCH ARTICLE
Year : 2013  |  Volume : 45  |  Issue : 3  |  Page : 223-226
 

Comparative evaluation of aqueous and plasma concentration of topical moxifloxacin alone and with flurbiprofen in patients of cataract


1 Department of Pharmacology, Malda Medical College, Malda, India
2 Department of Ophthalmology, R.G. Kar Medical College, Kolkata, India
3 Department of Pharmacology, Burdwan Medical College, Burdwan, India
4 Department of Pharmacology and Toxicology, West Bengal University of Animal and Fishery Sciences (WBUAFS), Kolkata, India
5 Department of Pharmacology, R.G. Kar Medical College, Kolkata, India

Date of Submission22-Jun-2012
Date of Decision30-Jan-2013
Date of Acceptance26-Feb-2013
Date of Web Publication15-May-2013

Correspondence Address:
Sujash Halder
Department of Pharmacology, Malda Medical College, Malda
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0253-7613.111900

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 » Abstract 

Objectives: To determine the aqueous and plasma concentrations of moxifloxacin administered topically alone and with flurbiprofen in patients undergoing cataract surgery.
Materials and Methods: A total of 50 subjects scheduled for routine cataract surgery were randomly allocated to two groups (n = 25 each). Group-1 patients were treated with topical moxifloxacin alone: One drop 6 times/day for 3 days before surgery and one drop 4 times on the day of surgery: Group-2 patients were treated with topical moxifloxacin as in Group-1 and with topical flurbiprofen: One drop 4 times/day for 3 days before and on the day of surgery. The interval between two drugs was 30 min for last 3 days and 15 min on the day of surgery. Last dose was administered 1 h before aqueous humor and blood sampling for both the groups. The antibiotic concentration in aqueous humor and plasma were determined by using high performance liquid chromatography.
Results: The mean concentration of moxifloxacin in aqueous humor was 1.71 ± 0.82 mg/ml in Group-1 and 2.39 ± 1.34 mg/ml in Group-2. Concentrations of moxifloxacin in aqueous humor were significantly higher in Group-2 than that of Group-1.
Conclusion: Flurbiprofen may increase the concentration of moxifloxacin in aqueous humor.


Keywords: Aqueous humor, cataract surgery, flurbiprofen, moxifloxacin


How to cite this article:
Halder S, Mondal KK, Biswas S, Mandal TK, Dutta BK, Haldar M. Comparative evaluation of aqueous and plasma concentration of topical moxifloxacin alone and with flurbiprofen in patients of cataract. Indian J Pharmacol 2013;45:223-6

How to cite this URL:
Halder S, Mondal KK, Biswas S, Mandal TK, Dutta BK, Haldar M. Comparative evaluation of aqueous and plasma concentration of topical moxifloxacin alone and with flurbiprofen in patients of cataract. Indian J Pharmacol [serial online] 2013 [cited 2019 Nov 22];45:223-6. Available from: http://www.ijp-online.com/text.asp?2013/45/3/223/111900



 » Introduction Top


Bacterial endophthalmitis is one of the most serious complications following intraocular operation like cataract surgery. The most common micro-organisms involved in endophthalmitis are either Gram-positive (e.g., Staphylococcus epidermidis, Staphylococcus aureus, Streptococci, Propionibacterium acnes) or Gram-negative (Pseudomonas aeruginosa, Haemophilus influenzae, and Serratia marcescens) bacteria. [1],[2] Systemically administered antibiotics have to penetrate the existing blood-ocular barriers to reach levels in the anterior chamber much higher than the minimal inhibitory concentrations (MICs) in order to eliminate the micro-organisms potentially. Second and third generation systemic fluoroquinolones have been found to have significant penetration into aqueous humor and less so into the vitreous body, with concentrations usually exceeding MICs of pathogens implicated in intraocular infections. [3],[4] Due to disadvantages of systemic routes, the topical ophthalmic preparations of fluoroquinolones were developed to achieve required concentration of drugs in aqueous humor for prevention of endophthalmitis. Moxifloxacin is a new fourth generation fluoroquinolone with a broad spectrum of activity. [5] It has been found to be the most potent fluoroquinolone for Gram-positive bacteria including methicillin resistant S. aureus and ciprofloxacin resistant S. aureus and equally potent as other fluoroquinolones against Gram-negative bacteria. [1] Central nervous system stimulating effect of some fluoroquinolones may be enhanced with co-administration of non-steroidal anti-inflammatory drugs (NSAIDs), resulting in neuroexcitation and/or seizures; but this effect has not been observed with moxifloxacin. [5] Flurbiprofen a NSAID, is used topically (eye drop) to maintain intraoperative mydriasis [6] and to prevent cystoid macular edema (CME), [7] pain and inflammation [8] following ophthalmological surgeries. With this knowledge a clinical study was designed to measure and evaluate the concentrations of topical moxifloxacin, used alone or with topical flurbiprofen, in the aqueous humor as well as in the blood simultaneously, collected just before cataract surgery.


 » Materials and Methods Top


This was a prospective, parallel, randomized, unicentric study carried out at Department of Pharmacology and Ophthalmology. For this study, patients undergoing routine cataract surgery in the Department of Ophthalmology were included. The protocol was approved by the Institutional Ethics Committee beforehand. After screening the patients per inclusion and exclusion criteria, 50 patients were randomly selected by the computer generated random number and the written informal consent were obtained from each of them. Individual case record form (CRF) was properly filled up from out-patient ticket and by interrogation of the patients. The patients include were above 40 years of age, undergoing cataract surgery and otherwise healthy. Patients with evidence of intraocular inflammation, hepatic or renal failure, or history of allergic reactions to fluoroquinolones, oral or topical antibiotic treatment for at least the preceding 2 weeks and previous operation in that eye were excluded. Patients were divided into two groups, each comprised of 25 patients. Group-1 patients received moxifloxacin eye drop (0.5%): One drop 6 times daily for 3 days before surgery and one drop 4 times on the day of surgery. Group-2 patients received moxifloxacin eye drop as in Group-1 and flurbiprofen eye drop (0.03%): One drop 4 times daily for 3 days before and on the day of surgery. Interval between topical moxifloxacin and flurbiprofen was 30 min for last 3 days and 15 min on the day of surgery. Last dose was administered 1 h before aqueous humor and blood sampling. Participants were scheduled to have extracapsular cataract extraction. While the patient was being prepared for operation after peribulbar anesthesia, 5 ml of blood was collected. At the initial stage of operation, 0.1 ml of aqueous humor was aspirated from the anterior chamber through a partial thickness limbal incision. Blood samples were centrifuged immediately afterwards for the separation of plasma. Then 0.5 ml of plasma was mixed with 1.5 ml of high performance liquid chromatography (HPLC) grade methanol (preservative) and 0.1 ml of aqueous humor was mixed with 0.5 ml of HPLC grade methanol. Both samples were stored at 2-8°C [9] and then transferred immediately with maintaining this temperature for analysis of drug by using HPLC according to method of Teja-Isavadharm et al. [10] with some modifications. The mobile phase consisted of 0.1 M phosphoric acid adjusted to pH 2.5 with a solution of 45% potassium hydroxide and acetonitrile mixed in a ratio of 70:30 (v/v). The flow rate of mobile phase was 1.2 mL/min and the eluent was monitored with diode array detector adjusted wavelength at 290 nm. This mixture was subjected to membrane filtration. Standard and sample (20 ml) were injected by Hamilton syringe into the injector port of liquid chromatograph. The residues were estimated after comparing with external standard.


 » Calibration Top


A stock solution of 100 ppm of analytical grade moxifloxacin was prepared in methanol as standard. The moxifloxacin concentration in plasma and aqueous humor was calculated using the following equation:



where a 1 is the area of standard chromatogram, a2 the area of sample chromatogram, V1 the initial volume of sample before processing (ml), V2 the final volume of sample after processing (ml), and C is the standard concentration of moxifloxacin (100 ppm).

Statistical analysis was done by Student's t-test (unpaired) to determine the level of significance. The P < 0.05 was considered as significant.


 » Results Top


Total 55 subjects were screened for the study, of which 50 (90.9%) were recruited - 25 in each group. After scrutinizing the CRF it was found that the patients of both two groups were comparable in terms of demographic [Table 1] and vital parameters [Table 2]. Mean concentration of moxifloxacin in aqueous humor and plasma in Group-1 and Group-2 patients are summarized in [Table 3] as well as depicted diagrammatically in [Figure 1]. It was found that the moxifloxacin level in aqueous humor was 1.71 ± 0.82 mg/ml in Group-1 and 2.39 ± 1.34 mg/ml in Group-2. A significantly (P < 0.05) 1.34-fold higher concentration of moxifloxacin in aqueous humor in presence of flurbiprofen of Group-2 patients was compared to patients of Group-1 (moxifloxacin alone). Interestingly, plasma concentration of moxifloxacin could not be detected in patients of Group-1 (alone) but it was detected among 12 out of 25 patients in Group-2 with a mean concentration of 0.44 ± 0.13 mg/ml (in presence of flurbiprofen).
Table 1: Demographic profile of recruited subjects (Group-1 and Group-2)


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Table 2: Vital parameters of recruited subjects (Group-1 and Group-2)


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Table 3: Mean moxifloxacin concentration (μg/ml) in aqueous humor and plasma following topical alone and with flurbiprofen in cataract patients (mean±SD)


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Figure 1: Comparison of mean concentration of moxifloxacin in aqueous humor between Group-1 and Group-2 patients

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 » Discussion Top


The goal of the study was to determine the aqueous as well as plasma concentration of moxifloxacin applied topically alone and with topical flurbiprofen. The plasma concentration difference was also compared. Antibiotic penetration and its concentration in aqueous humor in respect of different members of fluoroquinolones have been compared in several studies. [11] Few studies assessed and evaluated topical moxifloxacin concentration in aqueous humor. [12],[13] As moxifloxacin was found to be the most potent fluoroquinolone [1] and has been to have found high corneal permeability, [14] it was selected for the study. No other literature has been found to study moxifloxacin concentration co-administered with flurbiprofen are not available in literature. Even adequate information is not available regarding plasma concentration of moxifloxacin after topical administration. Prophylactic moxifloxacin treatment before cataract surgery provides optimal drug concentration in aqueous humor, which reduces bacterial population on eyelids, cornea, and conjunctiva. The optimal concentration is able to prevent development of post-operative endophthalmitis following cataract surgery. [14],[15] Topical flurbiprofen is now being used before cataract surgery to maintain intraoperative mydriasis and to prevent postoperative pain and inflammation. [6],[8] Flurbiprofen also may prevent development of CME. [7] Administration of topical agents on the day of surgery does not allow adequate exposure time; rather the agents being applied the days before surgery is more effective. [15] Based on this knowledge, both the drugs were started 3 days before surgery and few hours preoperatively on the day of surgery in different dose schedule in the study. This dose schedule of both drugs is usually followed for cataract surgery in our hospital.

The result of aqueous humor concentration of moxifloxacin in Group-1 in this study is comparable with other studies in the literature. [12],[13] The aqueous concentration of moxifloxacin was significantly (P < 0.05) higher in patients of Group-2 patients as compared to those of Group-1, suggesting flurbiprofen is hastens the absorption of moxifloxacin into the aqueous humor. Further, presence of moxifloxacin in plasma of a few patients of Group-2 indicates that flurbiprofen may have some role in enhancing the penetration of moxifloxacin through aqueous-blood barrier. The mechanism of this effect is unknown and further research is warranted to evaluate this effect further.


 » Acknowledgments Top


We are acknowledging the support and helps of the Department of Pharmacology and Ophthalmology, R. G. Kar Medical College and Hospital, Kolkata - 700 004 and also Department of Pharmacology and Toxicology, West Bengal University of Animal and Fishery Sciences, Kolkata - 700 037, India.

 
 » References Top

1.Mather R, Karenchak LM, Romanowski EG, Kowalski RP. Fourth generation fluoroquinolones: New weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol 2002;133:463-6.  Back to cited text no. 1
    
2.Soheilian M, Rafati N, Peyman GA. Prophylaxis of acute posttraumatic bacterial endophthalmitis with or without combined intraocular antibiotics: A prospective, double-masked randomized pilot study. Int Ophthalmol 2001;24:323-30.  Back to cited text no. 2
    
3.Donnenfeld ED, Perry HD, Snyder RW, Moadel R, Elsky M, Jones H. Intracorneal, aqueous humor, and vitreous humor penetration of topical and oral ofloxacin. Arch Ophthalmol 1997;115:173-6.  Back to cited text no. 3
    
4.Fiscella RG, Nguyen TK, Cwik MJ, Phillpotts BA, Friedlander SM, Alter DC, et al. Aqueous and vitreous penetration of levofloxacin after oral administration. Ophthalmology 1999;106:2286-90.  Back to cited text no. 4
    
5.Gatifloxacin and moxifloxacin: Two new fluoroquinolones. Med Lett Drugs Ther 2000;42:15-7.  Back to cited text no. 5
    
6.Keates RH, McGowan KA. Clinical trial of flurbiprofen to maintain pupillary dilation during cataract surgery. Ann Ophthalmol 1984;16:919-21.  Back to cited text no. 6
    
7.McColgin AZ, Raizman MB. Efficacy of topical voltaren in reducing the incidence of postoperative cystoid macular edema. Invest Ophthalmol Vis Sci 1999;40:S289.  Back to cited text no. 7
    
8.Sabiston D, Tessler H, Sumers K, Osterle C, Cheetham JK, Duzman E, et al. Reduction of inflammation following cataract surgery by the nonsteroidal anti-inflammatory drug, flurbiprofen. Ophthalmic Surg 1987;18:873-7.  Back to cited text no. 8
    
9.Bishara, R.H.: Good Cold Chain Management Practices for Clinical Trial Materials / Investigational Medicinal Products. American Pharmaceutical Outsourcing 2008;9:14-20.  Back to cited text no. 9
    
10.Teja-Isavadharm P, Keeratithakul D, Watt G, Webster HK, Edstein MD. Measurement of ciprofloxacin in human plasma, whole blood, and erythrocytes by high-performance liquid chromatography. Ther Drug Monit 1991;13:263-7.  Back to cited text no. 10
    
11.Solomon R, Donnenfeld ED, Perry HD, Snyder RW, Nedrud C, Stein J, et al. Penetration of topically applied gatifloxacin 0.3%, moxifloxacin 0.5%, and ciprofloxacin 0.3% into the aqueous humor. Ophthalmology 2005;112:466-9.  Back to cited text no. 11
    
12.Hariprasad SM, Blinder KJ, Shah GK, Apte RS, Rosenblatt B, Holekamp NM, et al. Penetration pharmacokinetics of topically administered 0.5% moxifloxacin ophthalmic solution in human aqueous and vitreous. Arch Ophthalmol 2005;123:39-44.  Back to cited text no. 12
    
13.Katz HR, Masket S, Lane SS, Sall K, Orr SC, Faulkner RD, et al. Absorption of topical moxifloxacin ophthalmic solution into human aqueous humor. Cornea 2005;24:955-8.  Back to cited text no. 13
    
14.Vasavada AR, Gajjar D, Raj SM, Vasavada V, Vasavada V. Comparison of 2 moxifloxacin regimens for preoperative prophylaxis: Prospective randomized triple-masked trial. Part 1: Aqueous concentration of moxifloxacin. J Cataract Refract Surg 2008;34:1379-82.  Back to cited text no. 14
    
15.Vasavada AR, Gajjar D, Raj SM, Vasavada V, Vasavada V. Comparison of 2 moxifloxacin regimens for preoperative prophylaxis: Prospective randomized triple-masked trial. Part 2: Residual conjunctival flora. J Cataract Refract Surg 2008;34:1383-8.  Back to cited text no. 15
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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