In vitro transcorneal permeation of ketorolac tromethamine from buffered and unbuffered aqueous ocular drops

In vitro transcorneal permeation of ketorolac tromethamine from 0.5% w/v solutions containing equimolar (0.02 M) concentrations of citrate (pH 6.5), phosphate (pH 6.5 and 7), citrate-phosphate (pH 7) and borate (pH 7) buffers was studied using goat cornea. Cumulative % permeation was maximum with phosphate buffered drops of pH 6.5. The effect of pH and ionic strength on permeation of ketorolac tromethamine from buffered (phosphate) drops was next investigated. Cumulative % permeation of ketorolac tromethamine from buffered drops was pH dependent being maximum at pH 4.5. Adjustment of ionic strength of drops to 0.2 resulted in decreased permeation of drug. Permeation of ketorolac tromethamine from unbuffered drops of varying pH and ionic strength 0.2 was also pH dependent and was maximum at pH 4.5. Buffered drops of pH between 4.5-5.5, ionic strength 0.2, provided better permeation of drug compared to unbuffered drops of same pH and ionic strength. Above pH 6.5 unbuffered drops showed better permeation than buffered drops. Increase in molarity of phosphate buffer (pH 4.5) used in making drops, between 0 to 0.15 M increased permeation. Aqueous drops of ketorolac tromethamine formulated in 0.15 M phosphate buffer of pH 4.5 and ionic strength 0.2 showed maximum cumulative % permeation in vitro. Considering lacrimation induced drug loss in vivo, by buffer of high concentration, ketorolac tromethamine drops formulated in buffer of low molarity, pH 4.5 and ionic strength 0.2 appear suitable.     

Effect of concentration, pH, and preservative on in vitro transcorneal permeation of ibuprofen and flurbiprofen from non-buffered aqueous drops

Influence of drug concentration, pH of aqueous drops and some commonly used preservatives on in vitro transcorneal permeation of ibuprofen and flurbiprofen were investigated using goat cornea. Increase in drug concentration in the drops made in normal saline resulted in increase in quantity permeated but decrease in cumulative percent permeation of both drugs. Permeation of each drug from 0.5% drops was maximum at acidic pH (6.4) and decreased with increase in pH of the drops. Normal saline, as a vehicle, favoured permeation of each drug, hence retained in the formulation. Benzalkonium chloride and chlorobutanol enhanced cumulative percent permeation of ibuprofen while benzalkonium chloride and phenyl mercuric nitrate increased permeation of flurbiprofen. Benzalkonium chloride being incompatible with 0.5% drops (pH 6.4) of either drug, chlorobutanol appears suitable for ibuprofen drops and phenyl mercuric nitrate for flurbiprofen drops.     

Transdermal delivery of ketorolac tromethamine: permeation enhancement, device design, and pharmacokinetics in healthy humans

Transdermal delivery of ketorolac tromethamine, a potent non-narcotic analgesic, through human skin in vitro and in vivo was investigated. In order to enhance and sustain the flux of ketorolac through human skin, various compositions of isopropyl alcohol (IPA), water, and isopropyl myristate (IPM) were evaluated. The solubility of ketorolac acid in an IPA/water binary vehicle mixture increased as the volume fraction of IPA increased from 0 to 90%. The solubility of ketorolac acid in an IPA/water/IPM (saturated) ternary vehicle mixture was practically the same as in the IPA/water binary vehicle mixture. The permeation of ketorolac acid through cadaver skin was evaluated using modified Franz diffusion cells. The skin flux increased as the IPA volume fraction was increased from 0 to 50% and then leveled off beyond 80% IPA loading. When IPM was added to the IPA/water binary vehicle mixture, a significant increase in the skin flux of ketorolac was observed. The skin flux decreased exponentially as the donor solution pH was raised from 3.5 to 7.0. The permeability of ketorolac through various membranes such as a microporous membrane and pressure-sensitive adhesive was evaluated. While a microporous membrane offered practically no diffusion resistance, the in vitro flux of ketorolac through cadaver skin decreased substantially upon lamination of pressure-sensitive adhesive onto a microporous membrane. Three liquid-reservoir type transdermal devices were fabricated using 6.5% ketorolac tromethamine gel, a microporous membrane, an adhesive membrane, and polyester backing film: TD-A (microporous membrane/acrylic adhesive), TD-B (microporous membrane/silicone adhesive), and TD-C (microporous membrane). The pharmacokinetics of ketorolac in 10 healthy humans following application of a transdermal device for 24 h was evaluated. The maximum plasma concentrations (Cmax) were 0.20, 0.18, and 0.82 microgram/mL for TD-A, TD-B, and TD-C, respectively. The total AUC values for the concentration-time curves were TD-C > TD-A > TD-B, and the terminal half-life ranged from 6.6 to 9.7 h.     

The maternal-to-zygotic transition in embryonic patterning of Caenorhabditis elegans

PURPOSE: To compare the analgesic efficacy and safety of nonpreserved ketorolac tromethamine 0.5% with those of its vehicle in the treatment of postsurgical ocular pain following radial keratotomy. METHODS: This study employed a multicenter, double-masked, randomized, parallel-group design. Radial keratotomy patients were treated with either nonpreserved ketorolac tromethamine 0.5% or its vehicle four times daily for up to 3 days following surgery. Patients were provided with an escape medication (acetaminophen) for use only as needed for intolerable pain. RESULTS: Patients treated with ketorolac reported significantly greater pain relief (P < or =.023), less pain intensity (P < or =.047), less use of escape medication (P < or =.001), fewer symptoms of ocular discomfort (P=.024), and fewer sleep disturbances (P < or =.013) than did patients treated with vehicle. No treatment-related adverse events were reported in the ketorolac group, and only one treatment-related adverse event was reported in the vehicle group. Most other safety findings were equivalent in the two treatment groups except that there were significantly less eyelid erythema (P=.026) and eyelid edema (P < or =.001) in the ketorolac group. CONCLUSIONS: Nonpreserved ketorolac tromethamine 0.5% ophthalmic solution was significantly more effective than, and as safe as, vehicle in the treatment of postoperative pain associated with radial keratotomy. Therefore, topical ketorolac may be a valuable treatment option for the maintenance of patient comfort following refractive surgery.     

Topical formulations of novel angiostatic steroids inhibit rabbit corneal neovascularization

PURPOSE: To evaluate the antiangiogenic potential of topical ophthalmic formulations of the novel angiostatic steroids AL-3789 and AL-4940, using a rabbit model of corneal neovascularization. METHODS: Neovascularization was induced in the rabbit cornea by surgical implantation of a standard ethylene vinyl acetate copolymer (Elvax-40) pellet containing 1 microg lipopolysaccharide. Coded formulations of the control vehicle or the following test agents were administered in prevention and intervention treatment protocols: 1% formulations of AL-3789, AL-4940, and cortisol acetate as a positive drug control. Three doses of AL-3789 (0.01%, 0.1%, and 1%) were also evaluated in a prevention treatment protocol. Corneal responses were monitored throughout a 2-week treatment period, and 1 week after the last treatment dose. Observations included quantitative measurement of the area of new blood vessel growth and qualitative assessment of cellular infiltrate and edema. All treatments and observations were performed in a double-masked manner. RESULTS: All tested formulations, except the vehicle and the 0.01% AL-3789 preparation, significantly inhibited corneal neovascularization and other lipopolysaccharide-induced responses in the various treatment protocols employed. AL-4940, the free alcohol form of AL-3789, was slightly less effective than cortisol acetate or AL-3789. The extent of inhibition of the angiogenic response by the 1% and 0.1% AL-3789 suspensions ranged from 76% to 100% 1 week after the last treatment. CONCLUSIONS: The antiangiogenic steroid AL-3789 may be a therapeutically useful angiostatic agent for corneal neovascularization and potentially could be effective in other ocular neovascular diseases.     

A new sesquiterpene ester from Celastrus orbiculatus reversing multidrug resistance in cancer cells

PURPOSE: To compare the healing of the cornea and the incidence of infection after traumatic corneal epithelial defect after single treatment with double bandage combined with either Fucithalmic single unit dose eye drops or chloramphenicol eye ointment. METHODS: This is a single-centre, randomised, single-blind, parallel-group study of 144 patients with accidental corneal abrasion or corpus alieni cornea who were referred to the Eye Department at Gentofte Hospital. The injured eye was examined with a photo slit-lamp before and 24 hours after treatment. The size of the abrasion was recorded and calculated on a PCX computerized video system and by slit-lamp photography. RESULTS & CONCLUSION: The Fucithalmic and chloramphenicol ointment treated groups showed no significant difference in corneal healing, local side effects, or signs of local infection.     

Seasonal variations in density of questing Ixodes ricinus (Acari: Ixodidae) nymphs and prevalence of infection with B. burgdorferi s.l. in south central Sweden

The pharmacokinetics and effects on platelet function of dipyrone (1.0 g; 2.5 g; i.v.) and ketorolac tromethamine (30 mg; i.m.) were studied in a three-way crossover study in twelve healthy subjects. The biosynthesis of thromboxane A2 in clotting whole blood ex vivo as well as collagen-induced platelet aggregation were determined before and up to 48 h after administration. Both prostanoid biosynthesis and platelet aggregation were inhibited by ketorolac tromethamine for a significantly longer period of time than by both doses of dipyrone. The changes in platelet functions correlated well with the serum concentrations of ketorolac or 4-methylaminoantipyrine and 4-aminoantipyrine. Using the sigmoidal Emax model the mean serum concentration (SD) of ketorolac, 4-methylaminoantipyrine and 4-aminoantipyrine inhibiting platelet TXB2 generation by 50% (EC50) in vitro was found to be 0.088 +/- 0.031, 1.2 +/- 0.3 and 10.2 +/- 3.4 micrograms ml-1, respectively. In conclusion the recovery of platelet function after dipyrone administration is faster as compared to ketorolac tromethamine. This is in line with clinical observations and may be an advantage when these drugs are given as postoperative analgesics at the doses tested.     

Biomimicry, dental implants and clinical trials

The overall objective of this study was to develop pluronic F127 (PF127)-containing formulations of pilocarpine hydrochloride (PHCL) suitable for controlled-release ocular delivery of PHCL. Various aqueous formulations were evaluated containing 1% w/v PHCL and 25% w/v PF127 alone or with one of the following additives present: poly(ethylene glycol) 4600 (PEG), poly(vinylpyrrolidone) 10,000 (PVP), poly(vinyl alcohol) 10,000 (PVA), methylcellulose 15 cP (MC), and hydroxypropyl methylcellulose 80-120 cP (HPMC). The in vitro dissolution of the PF127 formulations and the pilocarpine release profiles from them were obtained simultaneously at 34 degrees C and room temperature using a membraneless in vitro model. It was observed that the PEG- and PVP-containing PF127 formulations of PHCL dissolved the quickest and released the drug at a significantly faster rate than the control PF127 formulation, which had no additive present. The PF127 formulations of PHCL containing MC or HPMC exhibited the slowest dissolution rates and released the drug the slowest. The same rank order was observed at each temperature for the dissolution and PHCL release profiles of each formulation. On the basis of the in vitro results, the PF127 formulations of PHCL containing MC or HPMC as an additive showed potential for use as controlled-release ocular delivery systems for PHCL.     

The induction of lipid peroxidation in the serum of patients with acute peritonitis

Wound-healing activity of 2% betamicil ointment in comparison with the traditional stimulants of corneal repair regeneration (methyluracyl and solcoseril) was studied in experiments. The rate of epithelialization of a standard trephination wound in rabbit cornea (28 animals), mitotic activity of the anterior corneal epithelium, and strength of the regenerated tissue were assessed after use of different stimulants and in control. A maximal positive effect of local betamicil (2% ointment) was observed: the wounds epithelialized 57% sooner than in control, but there was no reliable difference from solcoseril; the regenerate of linear corneal wound was 1.5 times stronger. Use of this ointment in ophthalmology is validated.     

Percutaneous absorption of ibuprofen from different formulations. Comparative study with gel, hydrophilic ointment and emulsion cream

In a three-way cross-over study on 6 healthy adult volunteers, the percutaneous absorption of ibuprofen (CAS 15687-27-1) was studied with 3 topical formulations containing 5% w/w ibuprofen in a gel (Iprogel) or in a hydrophilic ointment or in an emulsion cream. By analysis of the plasma drug concentrations appearing after topical application, the relative drug bioavailability was calculated in terms of Cmax (maximum blood concentration of the drug), AUC (area under the curve of drug plasma concentrations at various time points) and Tmax (the time required for appearance of maximum drug concentration in the blood). The gel formulation showed the highest drug concentration in blood, reached in the shortest period, whereas that from the hydrophilic ointment showed the lowest drug concentration, reached at the slowest rate. The absorption from the reference product containing the drug as an o/w emulsion cream was less than with the gel formulation but higher than that found with the hydrophilic ointment.     

Role of oxidative stress in health and disease

BACKGROUND: Radiation therapy can cause corneal and conjunctival abnormalities that sometimes require surgical treatment. Corneal stem cell dysfunction is described, which recovered after the cessation of radiation. METHODS: A 44-year-old man developed a corneal epithelial abnormality associated with conjunctival and corneal inflammation following radiation therapy for maxillary cancer. He experienced ocular pain and loss of vision followed by conjunctival epithelialisation of the upper and lower parts of the cornea. RESULTS: Examination of brush cytology samples showed goblet cells in the upper and lower parts of the cornea, which showed increased fluorescein permeability, and intraepithelial lymphocytes. Impression cytology showed goblet cells in the same part of the cornea. Specular microscopy revealed spindle type epithelial cells. Patient follow up included artificial tears and an antibiotic ophthalmic ointment. The corneal abnormalities resolved after 4 months with improved visual acuity without any surgical intervention, but the disappearance of the palisades of Vogt did not recover at 1 year after radiation. CONCLUSION: Radiation therapy in this patient caused temporary stem cell dysfunction which resulted in conjunctivalisation in a part of the cornea. Although limbal stem cell function did not fully recover, this rare case suggested that medical options should be considered before surgery.     

Human corneal studies with a vitrification solution containing dimethyl sulfoxide, formamide, and 1,2-propanediol

We tested the tolerance of human corneas to a vitrification solution, modified VS41A, containing 3.1 M dimethyl sulfoxide, 3.1 M formamide, and 2.2 M 1,2-propanediol in a carrier solution consisting of the corneal storage medium CPTES with 2.5% w/v chondroitin sulfate. Seven human corneas were exposed for 10 min each to graded concentrations of the solution at 0 degree C, remaining in the full-strength solution for 10 min. The corneas had significantly more endothelial cell damage (P < 0.05) than seven mated control corneas, but it was minimal (4.3% cell loss). Attempts at vitrification and rewarming of three corneas exposed to the solution by this protocol, however, resulted in ice formation in the peripheral corneal stroma and severe endothelial damage. Presumably, equilibration with the cryoprotectant in the thicker periphery of the human cornea had not occurred. Ice did not form on the center of one cornea, and substantial numbers of central endothelial cells survived after vitrification in this case. Immersion of the human corneas for 25 min in each of the four graded solutions at 0 degree C was required for sufficient penetration of the cryoprotectant to allow total corneal vitrification and rewarming without ice formation. This prolonged exposure to modified VS41A caused unacceptable damage to the corneal endothelium, however. Successful vitrification of human corneas with this solution will require a safe method for obtaining corneal equilibration with the cryoprotectant.     

Identification of drugs in pharmaceutical dosage forms by X-ray powder diffractometry

A simple X-ray powder diffractometric (XRD) method was developed for the identification of the active ingredient in a variety of dosage forms. The method was successfully used to unambiguously identify the active ingredient(s) in tablet, capsule, suppository and ointment formulations. The unique feature of the method is that it provides information about the solid-state of the drug. Thus, a capsule formulation containing anhydrous ampicillin was readily distinguished from that containing ampicillin trihydrate. The USP stipulates the use of the beta-polymorphic form of anhydrous carbamazepine in carbamazepine tablets. Contamination by the alpha-polymorph (down to a level of 1.4% w/w of the formulation) could be detected. In some of the multicomponent formulations, there was a pronounced overlap of the powder patterns of ingredients which made identification difficult. This problem was solved by using a pattern subtraction technique, which permitted selective subtraction of the XRD pattern of the constituents of the formulation from the overall XRD pattern. Such an approach enabled identification of the drug even when it constituted only 5% w/w of the formulation. The method also permitted simultaneous identification of the multiple active ingredients in trimethoprim-sulfamethoxazole and acetaminophen-aspirin-caffeine formulations.     

Influence of alpha-cyclodextrin and hydroxyalkylated beta-cyclodextrin derivatives on the in vitro corneal uptake and permeation of aqueous pilocarpine-HCl solutions

Interactions in aqueous solution between pilocarpine hydrochloride (P-HCl), a rather hydrophilic drug with good water solubility, and various cyclodextrins (CDs) were described recently. To assess the influence of CDs on the diffusion behavior of pilocarpine, in vitro studies were performed using porcine or bovine corneas as diffusion barriers. The affinity of P-HCl for porcine cornea in the presence of alpha-cyclodextrin (alpha-CD) and (hydroxyethyl)-beta-cyclodextrin (HE-beta-CD) was determined by drug uptake experiments. Additionally, in vitro permeation experiments through bovine corneas were conducted with a modified diffusion device optimized for corneal perfusion studies. The results obtained from the corneal uptake studies indicate that the addition of alpha-CD led to increased tissue drug levels. The increase in permeability of pilocarpine in the presence of alpha-CD was approximately 10-fold (log Papp = -4.87 +/- 0.03) in comparison with plain P-HCl solution (log Papp = -5.89 +/- 0.06). Permeation studies with corneas pretreated with alpha-CD solution revealed enhanced corneal permeability of pilocarpine due to alpha-CD induced membrane effects. The hydroxyalkylated beta-CD derivatives HE-beta-CD (log Papp = -6.27 +/- 0.09) and (hydroxypropyl)-beta-cyclodextrin (HP-beta-CD; log Papp = -6.40 +/- 0.03), however, seemed to cause slightly decreased permeation rates, supporting the concept of an interaction between pilocarpine and the hydroxyalkylated-beta-CD derivatives. Considering physiological compatibility, the addition of CDs seems to be an effective tool to modify and optimize the ocular availability of pilocarpine.     

Racemization of ketorolac in aqueous solution

The racemization of ketorolac was studied in aqueous buffered solution at 25 and 80 degrees C and analyzed in detail with respect to the catalytic species in solution. The reaction has a U shaped pH rate profile at 80 degrees C with the pH of maximum stability occurring in the region of pH 3.0-7.5. A T90 value of 8 months was observed for a 1.5% (R)-ketorolac tromethamine solution at pH 7.4 and 25 degrees C. Additionally, the data shows that alternative salt forms are necessary in order to prepare a stable single isomer formulation. Alternative buffers, in particular phosphate buffer, provide formulations exhibiting a T90 greater than 2 years.     

Interposed bone grafts to accommodate endosteal implants for retaining mandibular overdentures. A 1-7 year follow-up study

STUDY OBJECTIVES: To examine the effect of timing of an intravenous (i.v.) dose (intraoperative vs. postoperative) of ketorolac tromethamine on pain scores and overall outcome after total abdominal hysterectomy (TAH) and myomectomy. DESIGN: Prospective, randomized, placebo-controlled study. PATIENTS: 248 ASA physical status I and II adult female patients scheduled for elective hysterectomy or myomectomy. INTERVENTIONS: General anesthesia was administered that consisted of thiopental sodium for induction, enflurane or isoflurane in nitrous oxide-oxygen for maintenance, and small doses of fentanyl and midazolam. Patients were randomized into three groups to receive toradol/placebo on a dosing schedule of dose 1 given one-half hour prior to expected end of surgery, dose 2 given on awakening in the postanesthesia care unit, and doses 3, 4, and 5 given at 6, 12, and 18 hours, respectively, after dose 2; Group 1 patients received placebo (saline) for dose 1, ketorolac 60 mg i.v. for dose 2, and ketorolac 30 mg i.v. for doses 3, 4, and 5. Group 2 patients received ketorolac 60 mg i.v. for dose 1, placebo for dose 2, and ketorolac 30 mg i.v. for doses 3, 4, and 5. Group 3 patients received placebo for all doses. All patients were given i.v. morphine PCA postoperatively, and morphine usages, visual analog pain intensity (VAS) scores, as well as adverse events and median times to recovery milestones were recorded. MEASUREMENTS AND MAIN RESULTS: VAS scores (mean) before dose 2 were significantly lower in Group 2 than Group 1, as were at-rest evaluations at 15 minutes and one hour. Group 2 patients also had decreased morphine requirements as compared to placebo. Both ketorolac groups (Groups 1 and 2) had significantly higher values for patient and observer overall ratings, case of nursing care, and tolerability as compared to placebo (Group 3). There were no significant differences among groups in adverse events or median times to recovery milestones. CONCLUSIONS: Although it is possible to demonstrate an improvement in early postoperative pain scores with intraoperative ketorolac and better overall ratings of ketorolac both intraoperatively and postoperatively as compared with placebo, the lack of clinically significant differences in analgesic efficacy in the two active study groups indicates the need for a careful consideration by the clinician of the risks versus benefits involved in the administration of antiplatelet medication in the perioperative period.     

The organization of the leuC, leuD and leuB genes of the extreme thermophile Thermus thermophilus

Rats fed a low-protein diet and administered 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione (NTBC) orally at 30 mumol/kg/day (10 mg/kg/day) or fed a low-protein diet containing 5 ppm NTBC develop lesions to the cornea of the eye within 3-8 days of exposure with an incidence of about 80%. This treatment also produces a marked inhibition of both hepatic and renal 4-hydroxyphenylpyruvate dioxygenase (HPPD) activity, an induction of hepatic but not renal tyrosine amino transferase activity, and a marked tyrosinemia in the plasma and aqueous humor. The extent of tyrosinemia and changes in the activity of tyrosine catabolic enzymes are similar to those reported for rats fed a normal protein diet and administered NTBC orally at 30 mumol/kg/day. However, the onset of corneal lesions occurs much earlier in rats fed a low-protein diet. The adverse ocular effects of NTBC can be alleviated by supplementing the low-protein diet with 1% w/w threonine. The protection afforded by threonine inclusion in the diet was not due to any amelioration in the extent of inhibition of hepatic HPPD activity or reduction in the extent of the tyrosinemia as measured 8 days after treatment. Rats fed L-tyrosine at 5% w/w in a low-protein diet rapidly develop lesions to the cornea of the eye, which are associated with a marked tyrosinemia, increased hepatic tyrosine aminotransferase activity, and about a 50% reduction in the activity of hepatic HPPD. The onset of corneal lesions produced by feeding a high tyrosine diet could be delayed, but not prevented, by inclusion of 1% w/w threonine in the low-protein diet. The basis for the beneficial effect of dietary supplementation of threonine in alleviating the corneal lesions produced by NTBC is unclear. However, our findings do illustrate that protein deficiency limits the ability of the rat to respond to a tyrosine load produced by inhibition of HPPD.     

Video laparoscopic adrenalectomy. The authors'' personal experience]

A prospective, randomized, open-label, single-dose study was conducted in an emergency department (ED) of a tertiary care teaching hospital to evaluate the efficacy of hyoscyamine sulfate as compared to ketorolac tromethamine for the reduction of pain from ureteral colic in the ED. Patients were included if they were at least 18 years of age and presented to the ED with an initial history and physical examination consistent with ureteral colic. Ureteral calculi were confirmed by ultrasound or intravenous urogram. Consecutive patients were randomized to either a single sublingual dose of 0.125 mg of hyoscyamine sulfate or a single intravenous dose of 30 mg of ketorolac tromethamine given over 1 minute. After 30 minutes, if analgesia was inadequate, patients were given rescue medication. Baseline pain scores were obtained using a horizontal, 100-mm visual analog scale. Additional pain scores were obtained at 10-minute intervals for 30 minutes. Upon completion of the study, both patients and physicians completed a global assessment score questionnaire. Fifty-four evaluable patients were randomized. Demographics and baseline pain scores were similar for each group. Decreasing trends in pain over time were observed for both treatment groups, with significantly greater pain reduction observed with ketorolac tromethamine as compared to hyoscyamine sulfate. Global evaluations of pain relief revealed better results in the ketorolac tromethamine group than in the hyoscyamine sulfate group, although this result was not statistically significant.     

Corneal neovascularization induced by xenografts or chemical cautery. Inhibition by cyclosporin A

PURPOSE: Neovascularization of the cornea occurs in numerous pathologic states causing decreased visual acuity and blindness and is a major complication of corneal allotransplantation. The purpose of this study was to investigate the effect of topical and systemic cyclosporin A (CsA) on corneal angiogenesis induced by xenotransplantation or by chemical cauterization. The subcutaneous disc angiogenesis system (DAS) also was used to study the effects of CsA on angiogenesis in a nonocular site. METHODS: Corneal angiogenesis was provoked by either xenotransplantation or chemical cautery. Rats from experiments using both of these models were subdivided into four treatment groups. Topical treatment was administered by using 4% CsA eye drops or vehicle (castor oil) four times daily for 10 days. Systemic therapy consisted of daily (5 mg/kg per day) subcutaneous injections of CsA or vehicle. In the DAS experiments, rats received CsA or vehicle systemically or intradisc. The amount of neovascularization was quantitated by digital image analysis in corneal flat preparations and sections of discs. RESULTS: Rats that received xenografts or cautery manifested less corneal neovascularization than did control animals after topical of subcutaneous CsA treatment. CsA also enhanced the survival of corneal xenografts. A difference between CsA and vehicle-treated animals in the DAS experiments was not detected. CONCLUSIONS: CsA effectively retards the growth of new vessels in the cornea after xenotransplantation or chemical cauterization and prolongs xenograft survival. However, CsA does not suppress angiogenesis in all systems, because it was ineffective in blocking vessel growth in the subcutaneous DAS.