Topical Losartan: Practical Guidance for Clinical Trials in the Prevention and Treatment of Corneal Scarring Fibrosis and Other Eye Diseases and Disorders

Abstract

Losartan is an angiotensin II receptor blocker (ARB) that impedes transforming growth factor (TGF) beta signaling by inhibiting activation of signal transduction molecule extracellular signal-regulated kinase (ERK). Studies supported the efficacy of topical losartan in decreasing scarring fibrosis after rabbit Descemetorhexis, alkali burn, and photorefractive keratectomy injuries, and in case reports of humans with scarring fibrosis after surgical complications. Clinical studies are needed to explore the efficacy and safety of topical losartan in the prevention and treatment of corneal scarring fibrosis, and other eye diseases and disorders where TGF beta has a role in pathophysiology. These include scarring fibrosis associated with corneal trauma, chemical burns, infections, surgical complications, and persistent epithelial defects, as well as conjunctival fibrotic diseases, such as ocular cicatricial pemphigoid and Stevens-Johnson syndrome. Research is also needed to explore the efficacy and safety of topical losartan for hypothesized treatment of transforming growth factor beta-induced (TGFBI)-related corneal dystrophies (Reis-Bu¨cklers corneal dystrophy, lattice corneal dystrophy type 1, and granular corneal dystrophies type 1 and type 2) where deposited mutant protein expression is modulated by TGF beta. Investigations could also explore the efficacy and safety of topical losartan treatments to reduce conjunctival bleb scarring and shunt encapsulation following glaucoma surgical procedures. Losartan and sustained release drug delivery devices could be efficacious in treating intraocular fibrotic diseases. Dosing suggestions and precautions that should be considered in trials of losartan are detailed. Losartan, as an adjuvant to current treatments, has the potential to augment pharmacological therapeutics for many ocular diseases and disorders where TGF beta plays a central role in pathophysiology.

Keywords: TGF beta; bullous pemphigoid; corneal fibrosis; glaucoma bleb fibrosis; losartan; persistent epithelial defect.

FIG. 1.

Images from representative corneas from the first experiments on the efficacy and safety of topical losartan used to treat stromal scarring fibrosis, in this case in rabbits, supported by a Department of Defense grant because of interest in posterior corneal injuries that could occur in military personnel in combination with anterior corneal trauma or chemical exposures. One month was chosen as the treatment time because that is when prior studies showed stromal fibrosis peaked in this rabbit model. In 1 eye of rabbits in surgery groups, an 8 mm diameter removal of the central Descemet's membrane and the attached corneal endothelium (DMR) was performed. Standardized slit lamp photographs of representative unwounded sham surgery corneas and corneas at 1 month after the DMR and treatment with topical and/or oral losartan solutions or the vehicle solutions beginning after surgery are shown. The sham unwounded control (Con) cornea groups were treated with (A) the oral high-dose (5 mg/kg) losartan 3 × per day or (B) topical 0.1 mg/mL losartan 6 × per day for 1 month. (C) A representative cornea that had DMR and was started on immediate treatment with topical vehicle 6 × per day for 1 month. The arrowheads denote neovascular blood vessels. (D) A representative cornea that had DMR and was immediately started on treatment with oral 5 mg/kg losartan 3 times a day for a month. Arrowheads indicate neovascularization. (E) A representative cornea that had the DMR and was started immediately on treatment with 0.1 mg/mL topical losartan 6 times a day for 1 month. Take note of the much greater transparency in the peripheral cornea compared to the topical vehicle treated cornea that had DMR (C) or the oral losartan treated cornea that had DMR (D) along with a measurable (ImageJ) decrease in the central opacity and a more central area of clearing (arrow). There was also a decrease in corneal neovascularization in these corneas compared with (C) or (D). (F) A representative cornea that had DMR and immediate treatment with both 0.1 mg/mL topical losartan 6 times a day and 5 mg/kg oral losartan 3 times a day. These corneas also had greater transparency of the peripheral cornea and a decrease in central opacity compared with (C, D) but were not significantly different from the corneas that had DMR and treatment with topical losartan alone. (E) An area of peripheral opacity clearing was also present in this cornea (arrow). Thus, high-dose oral losartan had no detectible effect on corneal stromal fibrosis after DMR. (G) A graph of the intensity of opacity measured with ImageJ in a 2.5 mm diameter circle for each cornea (representative circular areas of analysis are shown for each cornea). Means and standard errors for each group are shown. The * and ** indicate that the intensity of opacity for DMR treated with topical losartan and DMR treated with topical and oral losartan, respectively, were significantly different from the other groups, but were not significantly different from each other. DMR, Descemetorhexis; L or Los, losartan; OR, oral; T or TOP, topical; Un, sham unwounded. Reprinted with permission from Sampaio et al.

FIG. 2.

Losartan treatment of refractive surgery complications. (A) First human case of treatment of corneal scarring fibrosis with topical losartan. Slit lamp biomicroscopy of the cornea of a patient who developed severe corneal scarring after LASIK complicated by a free cap and severe diffuse lamellar keratitis. The patient began treatment with 1 drop of 0.8 mg/mL losartan in BSS 6 times per day 1.5 months after the complication. (B) A follow-up slit lamp photo after 4 months of 0.8 mg/mL of losartan in BSS 6 times per day shows there was a return of corneal transparency and improvement in both uncorrected and best-corrected visual acuity. (C) Many years after radial keratotomy, a patient reported decreasing uncorrected and best-corrected vision and was found to have developed fibrosis (arrows) within and surrounding an inferior incision. (D) After 1 drop of 0.8 mg/mL losartan in BSS 6 times per day for 15 days, there was already a notable decrease in scarring fibrosis (arrows). The arrowhead an artifact related to the light reflex during photography. The patient was lost to follow-up after the 15-day examination. (A, B) Reprinted with permission from Pereira-Souza et al. (C, D) Provided by the treating physicians Rodrigo Carlos de Oliveira, MD and Luiz Antônio Vieira, MD, Sao Paulo, Brazil. (A, B) 20 × Magnification. (C, D) 15 × Magnification. BSS, balanced salt solution; LASIK, laser-assisted in situ keratomileusis.

FIG. 3.

PEDs and myofibroblasts in corneas. (A) Slit lamp photo of a spontaneous PED that was still present in a rabbit cornea 3 weeks after moderate −4.5D PRK with a VISX S4 IR excimer laser. The epithelial defect is indicated by arrows and there is a thickened epithelial leading edge around the perimeter. The unepithelialized stroma of the PED was opaque and the opacity extended peripheral to the leading edge of the epithelial defect. Magnification 10 × . (B) Topical fluorescein staining of this cornea better revealed the epithelial defect. Magnification 10 × . (C) The same cornea had immunohistochemistry for the α-SMA marker for myofibroblasts (arrows) that are shown to populate the superficial stroma within the PED. Blue is DAPI that stains all cell nuclei. The leading edge of the epithelium (not shown) had poor adhesion and repeated artifactual dislocation from the underlying stroma in all sections cut with the cryostat. S is stroma. Magnification 400 × . (D) TEM of the same cornea. At this high magnification, the stroma (S) within the PED had an irregular surface with dense surface material (arrowheads). A large myofibroblast (M) was noted beneath the surface. Magnification 21,000 × . (E) At even higher magnification, the stromal surface within the PED again shows the increased density layer at the stromal surface (arrowheads). A small fragment of a myofibroblast (M) is also present. Magnification 42,000 × . (F) TEM shows the surface of the same rabbit cornea in the periphery of the excimer laser ablated PRK zone and 2 mm outside of the PED. Note there is a fully regenerated EBM with lamina lucida and lamina densa (arrows) at 3 weeks after the PRK. Also note that the uniform diameter and regular distribution of the collagen fibrils in this area of the stroma (S) in the transparent periphery compared with within the PED in (D). E is epithelium. Magnification 21,000 × . (G) TEM of the cornea from another rabbit that had not healed by 3 weeks after −4.5D PRK, and which also developed scarring fibrosis, despite the epithelial defect subsequently closing by 4 weeks after surgery. Within the scar, where the PED persisted for over 3 weeks, the anterior stroma was populated by layers of myofibroblasts (M), with highly disordered ECM between these cells. No EBM lamina lucida or lamina densa was detectible at their normal location beneath the epithelium (e). *Indicates an artifactual break in the tissue that occurred during cutting of the section due to weakening of the stroma by the disordered ECM laid down by myofibroblasts. Magnification 15,000 × . The presence of the myofibroblasts and stromal fibrosis at the surface within the epithelial defects of these corneas with PEDs likely contributes to epithelial nonhealing because the myofibroblasts do not produce HGF and KGF that subepithelial corneal fibroblasts normally would secrete in large amounts to modulate epithelial proliferation, motility, and differentiation.^, Treatment with topical losartan in these corneas with PEDs would likely lead to myofibroblast apoptosis and repopulation of the anterior stroma with normal corneal fibroblasts and keratocytes. That could facilitate healing of the PEDs, and clinical trials should be performed, with and without topical human NGF (Oxervate), to test this hypothesis and whether combined treatment with topical losartan and Oxervate could be an optimal therapy to not only heal the epithelial defect, but remove the scarring fibrosis that often limits vision even after eventual epithelial closure. α-SMA, alpha-smooth muscle actin; EBM, epithelial basement membrane; ECM, extracellular matrix; HGF, hepatocyte growth factor; KGF, keratinocyte growth factor; PED, Persistent epithelial defect; PRK, photorefractive keratectomy; TEM, transmission electron microscopy. Reprinted with permission from Wilson et al.

FIG. 4.

Slit lamp photographs of the corneal deposits in a patient with granular corneal dystrophy, type 1, who would be a good candidate for a trial of topical losartan treatment since the mutant TGFBI protein is modulated by TGF beta-1 and losartan is a known inhibitor of TGF beta-1 signaling. TGF, transforming growth factor; TGFBI, transforming growth factor beta-induced. This image graciously provided by Jeffrey M. Goshe, MD.