The Role of Prostaglandins in the Progression of Diabetic Retinopathy
| Status: | Recruiting |
|---|---|
| Conditions: | Ocular, Diabetes |
| Therapuetic Areas: | Endocrinology, Ophthalmology |
| Healthy: | No |
| Age Range: | 18 - 90 |
| Updated: | 4/21/2016 |
| Start Date: | March 2012 |
| End Date: | December 2016 |
| Contact: | Stephen J Kim, MD |
| Email: | steve.kim@vanderbilt.edu |
| Phone: | 615-936-2020 |
The Role of Prostaglandins in the Progression of Diabetic Retinopathy and the Therapeutic Efficacy of Topical Ketorolac (Acuvail)
Objective of the research study:
1. To measure anterior chamber and vitreous ketorolac (Acuvail®) concentrations after
topical administration in patients undergoing routine vitrectomy to determine the
ability of the medication to penetrate into the anterior chamber and vitreous cavity,
and to compare these levels to the IC50 for the cyclooxygenase-1 and -2 enzymes (COX-1
and COX-2)
2. To measure vitreous concentrations of prostaglandin subtypes (PGE, PGD, PGF) and other
inflammatory mediators (Interleukin-1β [IL-1β], IL-6, IL-8, tumor necrosis factor
[TNF]-α, VEGF) in both diabetic and nondiabetic patients undergoing vitrectomy
3. To determine if topical ketorolac (Acuvail®) can penetrate the anterior chamber and
vitreous cavity sufficiently to decrease levels of intraocular inflammatory mediators
that have been shown to be elevated in diabetic patients
4. To serve as a precursor to a 5-year longitudinal clinical trial to determine if
chronically administered topical ketorolac (Acuvail®) can prevent, delay or slow
diabetic retinopathy.
Research hypothesis
1. Ketorolac (Acuvail®) will penetrate the anterior chamber and vitreous cavity
sufficiently to achieve levels above the IC50 for COX-1 and COX-2
2. Prostaglandin and other inflammatory mediator levels in the anterior chamber and
vitreous cavity will be significantly higher among diabetic patients than nondiabetic
controls
3. Acuvail® can significantly lower anterior chamber and vitreous cavity levels of
prostaglandins and other inflammatory mediators in diabetic patients
1. To measure anterior chamber and vitreous ketorolac (Acuvail®) concentrations after
topical administration in patients undergoing routine vitrectomy to determine the
ability of the medication to penetrate into the anterior chamber and vitreous cavity,
and to compare these levels to the IC50 for the cyclooxygenase-1 and -2 enzymes (COX-1
and COX-2)
2. To measure vitreous concentrations of prostaglandin subtypes (PGE, PGD, PGF) and other
inflammatory mediators (Interleukin-1β [IL-1β], IL-6, IL-8, tumor necrosis factor
[TNF]-α, VEGF) in both diabetic and nondiabetic patients undergoing vitrectomy
3. To determine if topical ketorolac (Acuvail®) can penetrate the anterior chamber and
vitreous cavity sufficiently to decrease levels of intraocular inflammatory mediators
that have been shown to be elevated in diabetic patients
4. To serve as a precursor to a 5-year longitudinal clinical trial to determine if
chronically administered topical ketorolac (Acuvail®) can prevent, delay or slow
diabetic retinopathy.
Research hypothesis
1. Ketorolac (Acuvail®) will penetrate the anterior chamber and vitreous cavity
sufficiently to achieve levels above the IC50 for COX-1 and COX-2
2. Prostaglandin and other inflammatory mediator levels in the anterior chamber and
vitreous cavity will be significantly higher among diabetic patients than nondiabetic
controls
3. Acuvail® can significantly lower anterior chamber and vitreous cavity levels of
prostaglandins and other inflammatory mediators in diabetic patients
Patients who require vitrectomy for any indication and those meeting the inclusion/exclusion
criteria will be included. Patients will be consented to participate in the study and for
surgery.
Nondiabetic patients will be included in one of two groups. Twenty will receive topical
ketorolac (Acuvail®) preoperatively for 3 days and then samples will be taken at the time of
surgery. Twenty other patients will serve as controls for intraocular prostaglandin and
cytokine levels (to be compared to diabetic patients). This group will not receive
preoperative ketorolac (Acuvail®).
Diabetic patients will be included in one of two groups. Twenty patients will have
intraocular prostaglandin and cytokine levels measured. Twenty other patients will be in the
interventional group to determine if topical ketorolac (Acuvail®) can successfully lower
intraocular prostaglandin and inflammatory cytokine levels.
In all cases, patients are undergoing vitreoretinal surgery as the surgical treatment of
choice for their condition. For this study, undiluted samples will be drawn from the
vitreous cavity and anterior chamber at the beginning of the vitrectomy. These samples will
be stored, analyzed and frozen.
Samples will be tested for prostaglandin levels, in addition to other inflammatory
cytokines, and ketorolac levels.
Three days of Acuvail® given four times per day was chosen, as previous studies have shown
that one dose of ketorolac 0.4% achieves a peak aqueous concentration of 57.5 ng/mL,1 and
that 12 doses over two days achieves an aqueous concentration of 1079 ng/mL.2 Both values
are well above the IC50 for COX-1 (5.3 to 7.5 ng/mL) and COX-2 (33.9-45.2 ng/mL). The upper
end of this dosing spectrum was chosen, as more doses and a longer duration of therapy is
likely required to achieve sufficient vitreous levels to inhibit COX-1 and COX-2. This
dosing regimen was also used in another clinical study that assessed ketorolac levels and
prostaglandin levels in the vitreous cavity after topical administration four times a day
for three days preoperatively.3
criteria will be included. Patients will be consented to participate in the study and for
surgery.
Nondiabetic patients will be included in one of two groups. Twenty will receive topical
ketorolac (Acuvail®) preoperatively for 3 days and then samples will be taken at the time of
surgery. Twenty other patients will serve as controls for intraocular prostaglandin and
cytokine levels (to be compared to diabetic patients). This group will not receive
preoperative ketorolac (Acuvail®).
Diabetic patients will be included in one of two groups. Twenty patients will have
intraocular prostaglandin and cytokine levels measured. Twenty other patients will be in the
interventional group to determine if topical ketorolac (Acuvail®) can successfully lower
intraocular prostaglandin and inflammatory cytokine levels.
In all cases, patients are undergoing vitreoretinal surgery as the surgical treatment of
choice for their condition. For this study, undiluted samples will be drawn from the
vitreous cavity and anterior chamber at the beginning of the vitrectomy. These samples will
be stored, analyzed and frozen.
Samples will be tested for prostaglandin levels, in addition to other inflammatory
cytokines, and ketorolac levels.
Three days of Acuvail® given four times per day was chosen, as previous studies have shown
that one dose of ketorolac 0.4% achieves a peak aqueous concentration of 57.5 ng/mL,1 and
that 12 doses over two days achieves an aqueous concentration of 1079 ng/mL.2 Both values
are well above the IC50 for COX-1 (5.3 to 7.5 ng/mL) and COX-2 (33.9-45.2 ng/mL). The upper
end of this dosing spectrum was chosen, as more doses and a longer duration of therapy is
likely required to achieve sufficient vitreous levels to inhibit COX-1 and COX-2. This
dosing regimen was also used in another clinical study that assessed ketorolac levels and
prostaglandin levels in the vitreous cavity after topical administration four times a day
for three days preoperatively.3
Inclusion Criteria:
1. Adult patients aged 18 years or older who present for vitrectomy surgery for any
indication.
2. Diabetic and non-diabetic patients will be included.
Exclusion criteria:
1. Patients under the age of 18 years of age.
2. Pregnant women.
3. Patients with a history of vitrectomy surgery.
4. Current topical, periocular, intraocular or systemic corticosteroid use
5. Co-existent macular, retinovascular or ocular inflammatory disease (age-related
macular degeneration, retinal venous occlusive disease, uveitis, etc.)
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