Sustained release cyclosporine therapy for bilateral keratoconjunctivitis sicca in a red wolf (Canis rufus).
ABSTRACT A 12-yr-old intact male red wolf (Canis rufus) diagnosed with bilateral idiopathic dry eye was treated with subconjunctival drug delivery implants designed to release therapeutic levels of cyclosporine from 12-24 mo. Normal tear production and corneal health has been maintained, alleviating the need for daily handling of the animal for topical medication.
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ABSTRACT: Keratoconjunctivitis sicca is the major cause of chronic or recurrent conjunctivitis in dogs. The diagnosis of KCS is often delayed or mistaken for allergic or bacterial conjunctivitis and inappropriate or insufficient treatment leads to progressive corneal scarring and blindness in many dogs. The cause of KCS in dogs has not been proven, but evidence supports an immune-mediated etiology for the majority of cases. In an attempt to specifically treat the cause of KCS, a new immunosuppressant drug, cyclosporine, has been used in a topical preparation. Treatment results using ophthalmic cyclosporine are dramatic compared with historical treatments. Resolution of corneal scarring and increased lacrimation are seen in most dogs. Investigations of the mechanism of action of ophthalmic cyclosporine suggest the efficacy may have been serendipitous. A local neuroendocrine effect of cyclosporine on the lacrimal gland may actually be responsible for the increased lacrimation. Early diagnosis of KCS and treatment with ophthalmic cyclosporine may avert a major cause of blindness in dogs.Veterinary Clinics of North America Small Animal Practice 06/1990; 20(3):583-613. · 1.43 Impact Factor
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ABSTRACT: Thirty-six sequential cases of canine keratoconjunctivitis sicca (KCS) were treated with ophthalmic cyclosporine. The effects of topical cyclosporine were twofold: (1) cyclosporine increased tear production by 5 mm/min or greater in all cases of spontaneous KCS having an initial Schirmer's Tear Test value greater than 2 mm/min and in 59% of eyes with an initial Schirmer's Tear Test value of 0 to 2 mm/min, and (2) cyclosporine caused marked regression of chronic corneal neovascularization and granulation even in eyes in which lacrimation failed to improve. Additional benefits of topical cyclosporine were reduced mucopurulent conjunctivitis, rapid healing of nonhealing corneal ulcers, and reduced dependence on frequent topical treatments of KCS. Twelve normal beagles treated with topical cyclosporine also had a reversible increase in lacrimation compared with baseline or placebo control-treated dogs.Archives of Ophthalmology 09/1989; 107(8):1210-6. · 3.83 Impact Factor
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ABSTRACT: To develop a local drug delivery system that provides therapeutic cyclosporine levels to treat lacrimal gland graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Episcleral cyclosporine implants were manufactured with a silicone-based matrix design, and in vitro release rates were determined. Preclinical evaluation included toxicology (clinical examination, serial electroretinography, and histopathology) in normal rabbits and dogs, pharmacokinetics in normal rabbits, and pharmacodynamics in a canine model of aqueous tear deficiency and keratoconjunctivitis sicca. The cyclosporine implants showed sustained release of drug over time with in vitro assays. Histopathology showed normal ocular tissues in both dogs and rabbits 6 months after implantation. The cyclosporine implant produced lacrimal gland drug levels 1 to 2 log units higher than those reported with a variety of topical cyclosporine formulations and oral administration. The cyclosporine implant was effective in a canine model of keratoconjunctivitis sicca, with all animals able to discontinue topical cyclosporine and maintain normal Schirmer scores over a 6-month follow-up. This preclinical evaluation showed that the episcleral cyclosporine implant was safe, delivered potentially therapeutic cyclosporine levels to the lacrimal gland, and showed efficacy in a clinically relevant model of keratoconjunctivitis sicca. The episcleral cyclosporine implant shows promise in reducing the morbidity associated with lacrimal gland graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. In addition, continuous release of cyclosporine in the subconjunctival space with the episcleral implant was an effective means of delivering drug to the ocular surface and may have potential in treating other ocular inflammatory diseases.Investigative Ophthalmology & Visual Science 03/2005; 46(2):655-62. · 3.44 Impact Factor
Journal of Zoo and Wildlife Medicine 37(4): 562–564, 2006
Copyright 2006 by American Association of Zoo Veterinarians
SUSTAINED RELEASE CYCLOSPORINE THERAPY FOR
BILATERAL KERATOCONJUNCTIVITIS SICCA IN A RED WOLF
Anne E. Acton, D.V.M., A. Brady Beale, V.M.D., Brian C. Gilger, M.S., D.V.M., Dipl. A.C.V.O.,
and Michael K. Stoskopf, D.V.M., Ph.D., Dipl. A.C.Z.M.
Abstract: A 12-yr-old intact male red wolf (Canis rufus) diagnosed with bilateral idiopathic dry eye was treated
with subconjunctival drug delivery implants designed to release therapeutic levels of cyclosporine from 12–24 mo.
Normal tear production and corneal health has been maintained, alleviating the need for daily handling of the animal
for topical medication.
Key words: Canis rufus, cyclosporine, dry eye, keratoconjunctivitis sicca (KCS), sustained-release delivery, red
Keratoconjunctivitis sicca (KCS or ‘‘dry eye’’) is
defined by reduced production or increased evap-
oration of tears that result in damage to the corneal
surface. Tear film is comprised of a mucus layer
produced by conjunctival goblet cells, an aqueous
layer produced by the lacrimal and nicitans glands,
and a superficial lipid layer produced by meibom-
ian glands of the eyelids.4,8Inadequate production
of any of these layers or disorders that prevent the
complete closure of the eyelids disrupt the distri-
bution of the protective tear film across the globe.
If left untreated, poor lubrication can lead to chron-
ic corneal ulceration, ocular discomfort, corneal
edema, opportunistic infections, and eventual blind-
ness.1In domestic dogs (Canis lupus familiaris),
Schirmer tear test (STT) values of ?5 mm/min in-
dicate inadequate aqueous tear production, which is
the most common manifestation of KCS.2Current
medical management recommendations consist of
artificial tear replacement and the stimulation of
natural tear production with immunomodulating
agents such as cyclosporine.5These topical medi-
cations require lifelong daily administration, and
such frequent handling often is impractical in zoo
settings. This report outlines the successful man-
agement of bilateral KCS in a captive red wolf (Ca-
From the Environmental Medicine Consortium (Acton,
Gilger, Stoskopf), Department of Clinical Sciences, 4700
Hillsborough Street, College of Veterinary Medicine,
North Carolina State University, Raleigh, North Carolina,
27606, USA; and the Ophthalmology Service (Beale, Gil-
ger), Department of Clinical Sciences, 4700 Hillsborough
Street, College of Veterinary Medicine, North Carolina
State University, Raleigh, North Carolina, 27606, USA.
Correspondence should be directed to Dr. Acton.
nis rufus) using experimental, sustained-release cy-
closporine subconjunctival implants.
A 12-yr-old intact male red wolf (22 kg) housed
alone in an outdoor pen was noted to have focal
alopecia on the scalp and around both eyes in as-
sociation with recent excoriation. Closer inspection
under manual restraint revealed bilateral thick, yel-
low-green discharge at the medial canthi. Chemo-
sis, conjunctival vessel injection, and vasculariza-
tion of the dorsal limbus of the left cornea were
seen also. Both ear canals were malodorous with
excessive moist, brown exudate. The initial STT
revealed that tear production was 0 mm/min in both
eyes (OU). No fluorescein stain uptake was noted
in either eye. Cytologic examination of multiple su-
perficial and deep skin scrapings, as well as ear
swabs, revealed many gram-positive cocci and bud-
ding yeast (7–10/h.p.f.), degenerate neutrophils,
and occasional macrophages. No ectoparasites or
ova were seen. Initial treatment consisted of cefpo-
doxime proxetil (Simplicef?, Pfizer Animal Health,
New York, New York 10017, USA; 150 mg p.o.
s.i.d. ? 3 wk) for the pyoderma and a combination
ophthalmic regimen (OU s.i.d. ? 2 wk) consisting
of topical cyclosporine 0.2% ointment (Optimmu-
ne?, Schering-Plough Animal Health, Union, New
Jersey 07083, USA) and triple antibiotic ointment
with dexamethasone (Falcon Pharmaceuticals, Ltd.,
Ft. Worth, Texas 76134, USA) to treat the conjunc-
tivitis and to evaluate the animal’s response to cy-
closporine therapy prior to surgical placement of
bilateral subconjunctival drug delivery implants.
The animal tolerated daily capture and manual han-
dling for eye medications without incident.
The eyes showed marked improvement after 1
wk of daily topical therapy. Bilateral ocular dis-
charge ceased and conjunctival injection resolved.
Schirmer tear test results after 2 wk of topical ther-
ACTON ET AL.—SURGICAL MANAGEMENT OF DRY EYE IN A RED WOLF
tained-release implant through an incision in the dorsolat-
eral bulbar conjunctiva. The wolf is in right lateral recum-
bency with the left globe rotated ventrally.
Surgical placement of a cyclosporine sus-
apy were 15 mm/min OS and 16 mm/min OD,
which are baseline values in healthy domestic
dogs.2Intermittent fresh excoriations associated
with the dermatitis prompted the addition of keto-
conazole (PLIVA, Inc., East Hanover, New Jersey
07936, USA; 100 mg p.o. s.i.d. ? 3 wk) to the
treatment regimen. The wolf’s favorable response
to topical cyclosporine supported a decision to sur-
gically implant experimental cyclosporine delivery
devices designed to slowly release therapeutic lev-
els of the drug up to 12 mo.3Effective treatment
intervals as long as 24 mo have been observed in
beagles with these same implants (Gilger, unpubl.
The wolf was anesthetized with medetomidine
(Domitor?, Pfizer Animal Health, Exton, Pennsyl-
vania 19341, USA; 0.04 mg/kg i.m.) and butorpha-
nol (Torbugesic?, Ft. Dodge Animal Health, Ft.
Dodge, Iowa 50501, USA; 0.4 mg/kg i.m.) after an
overnight fast. Topical proparacaine HCl ophthal-
mic solution, 0.5% (Falcon Pharmaceuticals, Ft.
Worth, Texas 76134, USA) and topical phenyle-
pherine HCl 2.5% (Bausch & Lomb, Inc., Tampa,
Florida 33637, USA) were instilled in both eyes.
The skin around the surgical site was prepared with
dilute betadine solution and sterile saline. An eyelid
speculum provided maximum exposure of the
globe. A 2-mm incision was made into the dorso-
lateral bulbar conjunctiva 7 mm posterior to the
limbus. Westcott scissors were used to bluntly un-
dermine the conjunctiva medially and laterally. A
gamma-irradiated cyclosporine implant (13 mm
long ? 3 mm diameter, 10% matrix cyclosporine/
silicone) was inserted longitudinally into the sub-
conjunctival pocket (Fig. 1). The incision was
closed with a single cruciate 6-0 polygalactin su-
ture. Total surgery time for each eye was less than
10 min. Anesthesia was reversed with atipamezole
(Antisedan, Pfizer Animal Health, Exton, Pennsyl-
vania 19341, USA; 0.2 mg/kg i.m.). Postoperative
management included daily observation of the im-
plants for suture reaction or extrusion and appli-
cation of topical ophthalmic antibiotic ointment (E
Fougera & Co., Melville, New York 11747, USA;
OU s.i.d. ? 1 wk) to reduce the risk of infection.
Schirmer tear tests were repeated at regular inter-
vals. The implants could be visualized through the
conjunctiva by gently retracting the dorsal eyelid
and lightly depressing the globe with the lower eye-
lid. All oral medications were discontinued 1 wk
after surgery following resolution of the skin con-
dition. Schirmer tear tests were repeated at regular
intervals and were interpreted as normal (16 mm/
min OD and 18 mm/min OS) 2 wk postoperatively.
At 4 wk post-op, a small amount of dried yellow
discharge was detected at the medial canthus of the
left eye. The implant and suture were still clearly
visible, but chemosis had returned. The right eye
appeared normal. An STT yielded 9 mm/min OS
and 23 mm/min OD tear production. Mild conjunc-
tivitis was suspected, so treatment with topical an-
tibiotic with dexamethasone (s.i.d. OS ? 1 wk) was
resumed, following a negative fluorescein dye test,
and the ocular discharge resolved over 3–4 days.
Tear production immediately following the comple-
tion of supplemental therapy returned to normal (20
mm/min OS, 16 mm/min OD) and continued in the
normal range (16 mm/min OU) 1 wk later without
further treatment. Twelve months after surgery, tear
production remained ?13 mm/min OU with the cy-
closporine implants alone.
Most cases of KCS presumably result from an
immune-mediated response characterized by lym-
phocytic infiltrates and fibrosis in lacrimal acini
with subsequent conjunctival squamous metapla-
sia.1Immune-mediated diseases in humans have
been associated with KCS, including Sjo ¨gren-like
syndrome, lupus erythematosus, rheumatoid arthri-
tis, hypothyroidism, ulcerative colitis, diabetes mel-
litus, glomerulonephritis, and atopy.2Additional
etiologies for KCS in the dog include primary in-
fections (canine distemper virus, leshmaniasis),
drugs (sulfa, psychotropics, atropine, general an-
esthesia), neurogenic causes (facial nerve CN7, tri-
geminal nerve CN5), eyelid trauma, neoplasia, mu-
cin deficiency, irradiation, surgical removal of lac-
rimal glands, or breed predilections.1Eyelid anat-
omy and function were within normal limits in this
wolf and he was not on any medications known to
decrease tear production. Severe otitis media (left
JOURNAL OF ZOO AND WILDLIFE MEDICINE
ear) was diagnosed in this animal that potentially
affected the facial nerve innervation to the lacrimal
gland.1A thyroid panel at the time of surgery was
consistent with a diagnosis of a sick euthyroid syn-
drome in a domestic dog. This particular animal has
a history of persistent eosinophilia, despite the ab-
sence of fecal or ectoparasites, which could be con-
sistent with atopy and associated dry eye. Immune-
mediated KCS is, however, the most likely diag-
nosis in this animal and is often a diagnosis of ex-
clusion that can be confirmed by response to
Topical cyclosporine, a 1.2 kDa cyclic peptide,
has become the treatment of choice for KCS in ca-
nine patients.5It is a noncytotoxic, immunomodu-
lating drug that specifically inhibits the CD4? T-
helper cell production of certain cytokines (IL-2,
IL-6, macrophage activation factor), thereby inhib-
iting inflammation and T-cell proliferation. Cyclo-
sporine also inhibits rapid fibroblast and keratino-
cyte proliferation, while suppressing acinar and
conjunctival cell apoptosis so aqueous tear and mu-
cin production is preserved.6Cyclosporine increas-
es tear production within 2–3 wk of treatment ini-
tiation, whereas its discontinuation results in de-
creased tear production within 12–24 hr and a re-
currence of clinical signs.1Dogs receiving chronic
topical therapy (?5 yr) do not appear to become
refractory to the drug.7
Cyclosporine is lipophilic, making delivery of
therapeutic levels to ocular tissues challenging.
Systemic administration has caused toxic renal, he-
patic, and gastrointestinal side effects, and topical
administration often is cleared by the nasolacrimal
system or conjunctival blood supply before ade-
quate therapeutic levels can be achieved. The sub-
conjunctival device implanted in the wolf was de-
signed to slowly release cyclosporine locally; phar-
macodynamic studies performed in dogs demon-
strated that the implant released the drug at an
average rate of 20 ?g/day for the first month and
then tapered to a steady state of 10 ?g/day for at
least 6 mo, with no evidence of toxicity.3Clinical
trials in addition to the implanted wolf have shown
a positive response of STT values ?15 mm/min
sustained once topically applied cyclosporine has
been discontinued (Gilger, unpubl. data). The re-
sponse to sustained release cyclosporine implants
in this wolf provides encouraging documentation
for a practical treatment for immune-mediated KCS
in a zoo setting.
1. Kaswan, R. L., and M. A. Salisbury. 1990. A new
perspective on canine keratoconjunctivitis sicca: treatment
with ophthalmic cyclosporine. Vet. Clin. North Am. Small
Anim. Pract. 20: 583–625.
2. Kaswan, R. L., M. A. Salisbury, and D. A. Ward.
1989. Spontaneous canine keratoconjunctivitis sicca. A
useful model for human keratoconjunctivitis sicca: treat-
ment with cyclosporine eye drops. Arch. Ophthalmol.
3. Kim, H., K. G. Csaky, B. C. Gilger, J. P. Dunn, S.
S. Lee, M. Tremblay, F. de Monasterio, G. Tnasey, P.
Yuan, P. M. Bungay, R. J. Lutz, and M. R. Robinson.
2005. Preclinical evaluation of a novel episceral cyclo-
sporine implant for ocular graft-versus-host disease. In-
vest. Ophthalmol. Vis. Sci. 46: 655–662.
4. Lemp, M. A., and H. J. Blackman. 1983. Physiology
of tears. In: Milder, B., and B. A. Weil (eds.). The Lac-
rimal System. Appleton-Century-Crofts, Norwalk, Con-
necticut. Pp. 49–54.
5. Moore, C. P. 2000. Keratoconjunctivitis sicca. In:
Bonagura, J. D. (ed.). Kirk’s Current Veterinary Therapy
XIII: Small Animal Practice. W. B. Saunders Co., Phila-
delphia, Pennsylvania. Pp. 1061–1066.
6. Moore, C. P., J. B. McHugh, J. G. Thorne, and T. E.
Phillips. 2001. Effect of cyclosporine on conjunctival mu-
cin in a canine keratoconjunctivitis sicca model. Invest.
Ophthalmol. Vis. Sci. 42: 653–659.
7. Morgan, R. V., and K. L. Abrahms. 1991. Topical
administration of cyclosporine for treatment of keratocon-
junctivitis sicca in dogs. J. Am. Vet. Med. Assoc. 199:
8. Pflugfelder, S. C., A. Solomon, and M. E. Stern.
2000. The diagnosis and management of dry eye: a twen-
ty-five-year review. Cornea. 19: 644–649.
Received for publication 18 March 2006