Systemic Tetracycline Treatment of Alkali-Induced Corneal Ulceration in Rabbits

Seedor, John A.; Perry, Henry D.; McNamara, T. F.; Golub, Lorne M.; Buxton, Douglas F.; Guthrie, Debra S.

doi:10.1001/archopht.1987.01060020122043

Cited by 105 publications

(61 citation statements)

References 27 publications

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“…The compound 2-mercaptoacetyl-LPhe-L-Leu, an inhibitor of P. aeruginosa elastase (17), reduced the amount of corneal melting in experimental Pseudomonas keratitis in rabbits when combined with gentamicin (31). Recently, tetracycline was shown to reduce the incidence of alkali-induced corneal ulceration (30) and Pseudomonas keratitis-induced corneal perforation in rabbits (27). This effect was thought to be secondary to the anticollagenase effect of tetracycline.…”

supporting

confidence: 40%

Inhibition of Pseudomonas aeruginosa elastase and Pseudomonas keratitis using a thiol-based peptide

Burns

Paterson

Gray

et al. 1990

Antimicrob Agents Chemother

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Pseudomonas aeruginosa elastase is a zinc metalloproteinase which is released during P. aeruginosa infections. Pseudomonas keratitis, which occurs following contact lens-induced corneal trauma, can lead to rapid, liquefactive necrosis of the cornea. This destruction has been attributed to the release of both hostderived enzymes and the bacterial products P. aeruginosa elastase, alkaline protease, exotoxin A, and lipopolysaccharide endotoxin. A synthetic metalloproteinase inhibitor, HSCH2 (DL)CH[CH2CH(CH3)2]COPhe-Ala-NH2, which we previously showed to be a potent inhibitor of corneal coliagenase and alkali-induced corneal ulceration, was tested as a potential inhibitor of P. aeruginosa elastase. Inhibition constants (K,s) for the resolved diastereomers were determined with the chromogenic substrate furylacryloyl-glycyl-L-leucyl-Lalanine. One isomer had a K1 of 0.3 ,M, while the other had a Ki of 0.4 ,uM. The more potent diastereomer was evaluated in vivo in experimentally induced Pseudomonas keratitis in rabbits. Following inoculation of one cornea of each rabbit, topical treatment with a 1 mM solution of the inhibitor significantly delayed the onset of corneal melting and perforation, as compared with the results for the control and gentamicin-treated groups. This protective effect suggests that the inhibitor may have a therapeutic application by delaying the progression of corneal destruction in Pseudomonas keratitis.Pseudomonas aeruginosa is one of the most commonly encountered organisms found in infectious keratitis (26,28). Pseudomonas keratitis causes rapid, liquefactive destruction of the human cornea and is being seen with increasing frequency following corneal trauma from extended-wear contact lenses (7,12). Destruction of the cornea in Pseudomonas keratitis results from the release of degradative enzymes from both the organism (3,16,18,24) and hostderived sources (17). The metalloproteinase P. aeruginosa elastase is one of the main enzymes released by P. aeruginosa and is thought to be a major contributor to the pathogenesis of the organism (16,24).It has been demonstrated that immunization of rabbits and mice with elastase provides protection from Pseudomonas keratitis (25). Recent studies have suggested that inhibition of P. aeruginosa elastase may lead to more effective therapeutic approaches to this disease (19,21,22). Compounds which inhibit metalloproteinases such as P. aeruginosa elastase have been shown to alter the clinical course of Pseudomonas keratitis. The compound 2-mercaptoacetyl-LPhe-L-Leu, an inhibitor of P. aeruginosa elastase (17), reduced the amount of corneal melting in experimental Pseudomonas keratitis in rabbits when combined with gentamicin (31). Recently, tetracycline was shown to reduce the incidence of alkali-induced corneal ulceration (30) and Pseudomonas keratitis-induced corneal perforation in rabbits (27). This effect was thought to be secondary to the anticollagenase effect of tetracycline.The metalloproteinase inhibitor HSCH2 (DL)CH[CH2CH (CH3)2]CO-Phe-Ala-NH2 is a pote...

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supporting

confidence: 40%

Inhibition of Pseudomonas aeruginosa elastase and Pseudomonas keratitis using a thiol-based peptide

Burns

Paterson

Gray

et al. 1990

Antimicrob Agents Chemother

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“…The severity was classified as grade II in three eyes, Grade III in four eyes and Grade IV in eight eyes based on the criteria defined by the Roper-Hall. 12 Of the eight eyes in grade IV burns, five eyes had total limbal ischaemia (2,3,9,11,12). A total of five eyes had conjunctival ischaemia between 75 and 100%.…”

Section: Methodsmentioning

confidence: 99%

“…Medical treatment for acute ocular burns includes topical and systemic ascorbate, 1 citrate, 2 tetracycline, 3 and steroids. 4 Application of glued on-hard contact lens, 5 tenoplasty, 6 use of tissue adhesives, 7 and large-diameter keratoplasty 8 are some of the surgical procedures tried in the management of severe ocular burns.…”

Section: Introductionmentioning

confidence: 99%

Amniotic membrane transplantation in acute chemical burns

Arora

Mehta

Jain

2004

Eye

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“…Doxycycline was discovered in the early 1960's as a semisynthetic long-acting tetracycline derivative useful as a bacterial ribosome inhibitor in a wide variety of microbes. In subantimicrobial doses it is also an effective primary treatment for rosacea, sterile corneal ulceration, and effective adjunctive treatment for adult periodontitis (84)(85)(86) . Doxycycline has been shown to effectively inhibit MMP-9 in a wide variety of mouse and human cells including prostate epithelium, epidermal keratinocytes, and the aortic endothelium (87)(88)(89)(90) .…”

Section: Tetracyclines and Their Derivativesmentioning

confidence: 44%