Corneal Safety of Topically Applied Naltrexone

Zagon, Ian S.; Klocek, Matthew S.; Sassani, Joseph W.; Mauger, David T.; McLaughlin, Patricia J.

doi:10.1089/jop.2006.22.377

Cited by 25 publications

(50 citation statements)

References 28 publications

(33 reference statements)

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“…Topically applied NTX for 7 days (4 times per day) has been shown to an efficacious and safe treatment for abraded corneas of animals that were normal (non-diabetic), diabetic and hyperglycemic, and diabetic but normoglycemic through the use of insulin (Zagon et al, 2006b, Klocek et al, 2007). These findings were determined using a variety of non-invasive and invasive measures, and the results suggest that NTX is safe for topical use across a wide range of biological conditions.…”

Section: Introductionmentioning

confidence: 99%

Naltrexone and insulin are independently effective but not additive in accelerating corneal epithelial healing in type I diabetic rats

Klocek

Sassani

McLaughlin

et al. 2009

Experimental Eye Research

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Patients with diabetes are at increased risk for developing corneal disorders, termed diabetic keratopathy. Treatments for diabetic keratopathy are limited. Preclinical studies have demonstrated that topical administration of either naltrexone (NTX) or insulin (INS) accelerates corneal reepithelialization in Type I diabetic rats. This study determined whether the combination of NTX and INS would have additive effect(s) on the reepithelialization of corneal abrasions in diabetic male Sprague-Dawley rats beyond either agent alone. Type 1 diabetes (DB) (glucose levels >400 mg/dl) was induced with streptozotocin; glycemic levels were not controlled with INS. Eight weeks after induction of diabetes, a 5 mm diameter circular abrasion was created in the center of the cornea in one eye of each rat. Eye drops (0.05 ml) of INS [1U (~ 6 nM)] and NTX (10 −5 M) in Vigamox were administered separately 4 times daily for 7 days (NTX/INS); DB control rats received drops of sterile vehicle (DB SV) 4 times daily. Two other groups of rats were given only NTX (DB NTX) or only INS (DB INS). Reepithelialization was monitored by fluorescein staining, and images were recorded with a CCD camera. Areal measurements were made using Optimas software, and the percentage of epithelial defect over a 40 hr period was calculated. Twenty-four hr after formation of an abrasion (~21.7±0.4 mm 2 area), corneal wounds in DB rats treated with NTX, INS, or NTX/INS were significantly smaller (p<0.001) than those in DB SV rats, with reductions in the size of the defect ranging from 24-84%. DB rats treated with NTX or INS alone also were observed to have reductions in wound size of 22 and 29%, respectively, from subjects in the DB SV group at 16 h. At 16 h both the DB NTX and DB INS groups had defects that were 13 and 27%, respectively, smaller than those for the DB NTX/INS group, and at 40 h the DB INS animals had 78% smaller corneal wounds than in the DB NTX/INS group. Therefore, the DB NTX/INS group exhibited some slight delays in wound repair compared to the DB NTX and DB INS groups. Topical application of NTX and/or INS to the cornea had no effect on non-invasive measures that included ocular morphology, intraocular pressure, or corneal thickness. These data demonstrate that although NTX or INS accelerate wound healing, concomitant application of NTX and INS to corneal abrasions in diabetic animals does not have an additive effect on reepithelialization.

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Section: Introductionmentioning

confidence: 99%

Naltrexone and insulin are independently effective but not additive in accelerating corneal epithelial healing in type I diabetic rats

Klocek

Sassani

McLaughlin

et al. 2009

Experimental Eye Research

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“…Therefore, topical application of NTX over a 10,000-fold range of dosage had no overt toxicity for the parameters studied in rats. 54 Thus, our animals studies would predict no significant ocular toxicity from the course of treatment proposed in this study. Moreover, as noted above, NTX is approved for chronic systemic administration in the treatment of drug and alcohol abuse.…”

Section: Risks and Discomfortsmentioning

confidence: 77%

“…Therefore, topical application of NTX over a 10,000-fold range of dosage had no overt toxicity for the parameters studied. 54 Moreover, such therapy does not compromise adhesion complexes in normal or diabetic corneal epithelium. 55 …”

Section: F Iogrs and Corneal Epithelial Wound Healing In Diabetesmentioning

confidence: 99%

Ocular safety of Topical Naltrexone

Sassani¹,

Liang²,

Bowie³

2011

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel CommandFort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTDuring the past year we have obtained approval from our institutional and University Conflict of Interest Committees, which limited the ability of Dr. Sassani to actively participate in data collection or interpretation in the study. In order to compensate for this reduction in effective researchers, Dr. Esther Bowie, an Ophthalmologist on the faculty of our Department of Ophthalmology, will assist Dr. David Liang in performing the clinical studies and data collection.To date we have completed our first cohort of 4 volunteers at the once daily, 1 x 10-6 dosage, of topical Naltrexone in Vigamox® eyedrops in one eye of each volunteer. No untoward side effects were noted in this group of volunteers. We also have recruited and treated three patients for the second cohort who have completed the treatment schedule. We need to recruit one more volunteer for this cohort and complete the other three cohorts.We are committed to completing the study, and have requested a one year extension of the grant period with no additional funds in order to complete our study. Dr. Sassani and his associates have been funded to perform a Phase I Clinical Trial of Naltrexone dissolved in Vigamox® and applied topically as eye drops preliminary to a therapeutic trial of that medication in the treatment of corneal epithelial defects in diabetic individuals. During the past year, we have obtained Institutional and University Conflict of Interest approval for our study. As a result, Dr. Sassani has elected not to participate directly in data collection for the study. We have recruited Dr. Esther Bowie, an Ophthalmologist in the Department of Ophthalmology to assist Dr. Liang in volunteer examination and data collection. The recruitment of Dr. Bowie, who has a clinic schedule that complements that of Dr. Liang, should facilitate the examination of volunteers. SUBJECT TERMS Body:Background: Over the past 18 years, Dr. Sassani has worked with Dr. Zagon's research team delineating the role of the Opioid Growth Regulatory System in corneal epithelial homeostasis and wound healing. We have demonstrated that the native opioid peptide, [Met 5 ]-enkephalin, termed opioid growth factor (OGF) is a tonically active, rece...

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“…A comprehensive series of investigations have been conducted on the role of the OGF-OGFr axis to repair ocular surface abnormalities [51][52][53][54][55][56][61][62][63][64]. Corneal surface integrity maintains the required barrier to enable vision.…”

Section: Continuous Ogfr Blockade: Ocular Surface Wounds and Dry Eyementioning

confidence: 99%

“…Complete blockade of the OGFr by naltrexone also enhanced corneal surface wound repair in alloxan-induced type 1 diabetic rabbits [64], and genetically hyperglycemic type 2 diabetic mice [63]. A concern of whether chronic exposure to naltrexone was detrimental leading to scarring or exuberant granulation tissue in the corneal stroma was 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 17 addressed [54,63], and the safety of topical naltrexone was demonstrated in several animal models [51,52,64]. It appears that naltrexone accelerates cellular proliferation, but other intrinsic factors provide the "brakes"…”

Section: Continuous Ogfr Blockade: Ocular Surface Wounds and Dry Eyementioning

confidence: 99%

Duration of opioid receptor blockade determines biotherapeutic response

McLaughlin

Zagon

2015

Biochemical Pharmacology

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Corneal Safety of Topically Applied Naltrexone

Abstract: Topical application of NTX over a 10,000-fold range of dosage had no overt toxicity for the parameters studied, indicating that efficacy studies for the use of NTX in corneal wound healing are warranted.

Cited by 25 publications

References 28 publications

Naltrexone and insulin are independently effective but not additive in accelerating corneal epithelial healing in type I diabetic rats

Naltrexone and insulin are independently effective but not additive in accelerating corneal epithelial healing in type I diabetic rats

Ocular safety of Topical Naltrexone

Duration of opioid receptor blockade determines biotherapeutic response

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