Prednisolone Phosphate Research Articles

Effectiveness of specific antibiotic/steroid combinations for therapy of experimental Pseudomonas aeruginosa keratitis.

Ciprofloxacin and prednisolone, but not an aminoglycoside and dexamethasone, were previously found to be effective in killing bacteria and reducing inflammation for the treatment of Pseudomonas keratitis. We investigated the therapeutic effectiveness of tobramycin/prednisolone and ciprofloxacin/dexamethasone in a rabbit model of experimental keratitis to increase our understanding of the effectiveness of antibiotic/steroid combinations. To our knowledge, this is the first analysis of the effectiveness of a combination of ciprofloxacin and dexamethasone for experimental keratitis. Two experiments were conducted. In the first experiment, 36 rabbits were divided into six groups: 1) untreated; 2) prednisolone acetate, 1.0%; 3) prednisolone phosphate, 1.0%; 4) tobramycin, 1.36%; 5) tobramycin plus prednisolone acetate; 6) tobramycin plus prednisolone phosphate. In the second experiment, 23 rabbits were divided into four groups: 1) untreated; 2) ciprofloxacin, 0.3%, plus dexamethasone alcohol, 0.1%; 3) ciprofloxacin; 4) dexamethasone alcohol. Topical antibiotic and/or steroid was given for 10 h, from 16 to 26 h postinfection, one drop every 15 min for the first hour and then every 30 min for the remaining 9 h. At 27 h postinfection, eyes were evaluated by slit lamp examination (SLE) and assayed for the presence of bacteria in terms of colony forming units (CFU) per cornea. Both prednisolone acetate and prednisolone phosphate reduced ocular inflammation (as determined by SLE), compared with no treatment (P < or = 0.036); the phosphate was more effective (P = 0.005). Tobramycin alone and in combination with prednisolone also significantly reduced SLE, compared with no treatment (P < or = 0.006). The bactericidal activity of tobramycin was not affected by either steroid formulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Herpetic Eye Disease Study: A Controlled Trial of Topical Corticosteroids for Herpes Simplex Stromal Keratitis

To evaluate the efficacy of topical corticosteroids in treating herpes simplex stromal keratitis. The authors performed a randomized, double-masked, placebo-controlled, multicenter clinical trial of 106 patients with active herpes simplex stromal keratitis who had not received any corticosteroids for at least 10 days before study enrollment. Patients were assigned to the placebo group (n = 49) or the steroid group (topical prednisolone phosphate; n = 57); both regimens were tapered over 10 weeks. Both groups received topical trifluridine. Visual acuity assessment and slit-lamp biomicroscopy were performed weekly for 10 weeks, every other week for an additional 6 weeks or until removal from the trial, and at 6 months after randomization. The time to treatment failure (defined by specific criteria as persistent or progressive stromal keratouveitis or an adverse event) was significantly longer in the steroid group compared with the placebo group. Compared with placebo, corticosteroid therapy reduced the risk of persistent or progressive stromal keratouveitis by 68%. The time from randomization to resolution of stromal keratitis and uveitis was significantly shorter in the steroid group compared with the placebo group even though both groups included patients who were removed from the study and treated with topical corticosteroids according to best medical judgment. Nineteen (33%) of the steroid-treated patients and 11 (22%) of the placebo-treated patients completed the 10 weeks of protocol therapy and had stable, noninflamed corneas after 16 weeks. At 6 months after randomization, no clinically or statistically significant differences in visual outcome or recurrent herpetic eye disease were identified between the steroid and placebo groups. The topical corticosteroid regimen used in this study was significantly better than placebo in reducing persistence or progression of stromal inflammation and in shortening the duration of herpes simplex stromal keratitis. Postponing steroids during careful observation for a few weeks delayed resolution of stromal keratitis but had no detrimental effect as assessed by visual outcome at 6 months.

Herpetic Eye Disease Study: A Controlled Trial of Oral Acyclovir for Herpes Simplex Stromal Keratitis

To evaluate the efficacy of oral acyclovir in treating stromal keratitis caused by herpes simplex virus (HSV) in patients receiving concomitant topical corticosteroids and trifluridine. The authors performed a randomized, double-masked, placebo-controlled, multicenter trial in 104 patients with HSV stromal keratitis without accompanying HSV epithelial keratitis. Sample size was chosen so that a 5%, one-tailed test would have an 80% chance of detecting a doubling of the median time to treatment failure. Patients were randomized to receive a 10-week course of either oral acyclovir (400 mg 5 times daily, n = 51) or placebo (n = 53). All patients also received a standard regimen of topical prednisolone phosphate and trifluridine. Ophthalmologic examinations were performed weekly during the 10-week treatment period, every 2 weeks for an additional 6 weeks, and at 6 months after entry into the trial. The median time to treatment failure (defined as worsening or no improvement of stromal keratitis or an adverse event) was 84 days (95% confidence interval, 69-93 days) for the acyclovir group and 62 days (95% confidence interval, 57-90 days) for the placebo group. By 16 weeks, 38 patients (75%) in the acyclovir group and 39 patients (74%) in the placebo group had failed treatment. Also by that time, the keratitis had resolved with trial medications, and there was no subsequent worsening in nine patients (18%) in the acyclovir group and ten (19%) in the placebo group. None of these results were significantly different between the two groups. However, visual acuity improved over 6 months in significantly more patients in the acyclovir group than in the placebo group. There was no statistically or clinically significant beneficial effect of oral acyclovir in treating HSV stromal keratitis in patients receiving concomitant topical corticosteroids and trifluridine with regard to time to treatment failure, proportion of patients who failed treatment, proportion of patients whose keratitis resolved, time to resolution, or 6-month best-corrected visual acuity. Visual acuity improved over 6 months in more patients in the acyclovir group than in the placebo group.

Band Keratopathy Secondary to Herpes Simplex or Topical Corticosteroid?

I wish to make the following comments with regard to the article by Brik and associates 1 in the April 1993 issue of theArchives. The rapid development of what can be characterized as band keratopathy in the two patients described in their report was previously noted under other circumstances, particularly in patients with severely dry eyes. 2 Recently, a number of similar cases were reported at the annual meeting of the Eye Bank Association of America, abstracts of which were published. 3 An article in theArchivesfurther illustrated this problem. 4 The patients described developed corneal calcification in association with steroidphosphate preparations, particularly when used in the treatment of herpetic keratitis. I treated a patient with herpes zoster with prednisolone phosphate who rapidly developed a calcific cornea severe enough to require a penetrating keratoplasty. It has been suggested that phosphate precipitation may be responsible for this phenomenon. It

Budesonide for the Treatment of Inflammatory Bowel Disease

While corticosteroids are the most effective treatment for the symptomatic management of patients with inflammatory bowel disease (IBD), they cause serious side effects. Budesonide is a nonhalogenated glucocorticosteroid structurally related to 16 alpha-hydroxyprednisolone that possesses high topical anti-inflammatory activity and low systemic activity compared with the conventional steroids prednisone and prednisolone. This favourable activity ratio is achieved because a high affinity to the steroid receptor is coupled with rapid hepatic conversion to metabolites with minimal or no biological activity. Controlled trials in patients with distal ulcerative colitis indicate that budesonide enemas have equivalent or superior efficacy compared with 5-aminosalicylic acid (5-ASA) enemas, prednisolone disodium phosphate enemas or methylprednisolone enemas, without causing significant depression of endogenous cortisol levels. Two controlled trials investigating the efficacy of an oral controlled-ileal release form of hudesonide for active Crohn’s disease have recently been completed. In the first trial, after eight weeks’ treatment budesonide 9 mg daily caused clinical remission in 51% of patients, compared with 20% of patients receiving placebo. Budesonide caused a dose-related reduction of plasma cortisol responses to adrenocorticotropic hormone stimulation, but was not associated with clinically important corticosteroid-related symptom or other toxicity. In a second trial, budesonide 9 mg daily was as effective as prednisolone for induction of remission in active ileocecal Crohn’s disease. Budesonide is a potentially promising new therapeutic agent for the management of patients with IBD.

Ketoconazole and Fluconazole Drug Interactions

This article reviews potential drug interactions that exist between ketoconazole or fluconazole and other drugs. English-language data sources included human subjects' computerized databases and published indexes. Case reports and studies demonstrate decreased dosage requirements of cyclosporine sodium, methylprednisolone sodium succinate, and possibly anticoagulants and phenytoin after ketoconazole or fluconazole administration, suggesting hepatic enzyme inhibition. Increased dosage requirements of ketoconazole are necessary after rifampin administration, suggesting rifampin's induction of hepatic microsomal enzymes. Possibly a similar effect may occur with concomitant fluconazole and rifampin. The effect of ketoconazole administration on prednisolone sodium phosphate and theophylline warrants further study. Fluconazole, a more selective agent for fungal P-450, seems to be of less concern regarding the potential for drug interactions than ketoconazole.

Corneal endothelial cell transplantation using Descemet's membrane as a carrier

Rabbit corneal endothelial cells were transplanted into the right eyes of four New Zealand white rabbits using bovine Descemet's membrane as a cell carrier. Descemet's membranes were dissected from cow eyes, flattened on 36 mm culture dishes, and cut into discs with a 6 mm trephine. Rabbit corneal endothelial cells were seeded onto the discs and maintained in tissue culture conditions for seven days until a complete monolayer with a cell density of 3,000 cells/mm2 was formed. Before transplantation, corneal edema was induced in the host animals by an endothelial scrape wound, which removed the corneal endothelium. Five weeks later, the animals were prepared for transplantation. A corneal button was cut and placed on a dissection table so the host Descemet's membrane could be removed. The donor Descemet's membrane with a complete monolayer of rabbit corneal endothelial cells was placed on the stroma of the corneal button. To keep the donor membrane in place, the button was cauterized at three peripheral points and sutured back into the host eye. Prednisolone sodium phosphate eyedrops and dexamethasone eyedrops and ointment were applied twice daily during the postoperative period. All grafts stayed clear for a period of 12 to 17 weeks. This study shows the potential for using Descemet's membrane as a carrier for corneal endothelial cell transplantation.

Pharmacokinetics of prednisolone transfer to breast milk

Prednisolone transfer to breast milk was studied in three nursing women who required oral steroid therapy for asthma. Each patient received a 50 mg intravenous dose of prednisolone phosphate, and blood and breast milk were sampled for 6 hours. Concentrations of prednisolone in milk declined more rapidly than in serum but were similar to expected unbound serum concentrations, suggesting that exchange between unbound prednisolone in serum and breast milk is relatively rapid and bidirectional. Because an average of 0.025% (range, 0.010% to 0.049%) of the prednisolone dose was recovered in milk, prednisolone transfer to breast milk does not appear to pose a clinically significant risk to nursing infants.

Prednisolone acetate or prednisolone phosphate concurrently administered with ciprofloxacin for the therapy of experimental Pseudomonas aeruginosa keratitis.

This study was conducted to determine the therapeutic efficacy of 3.0 mg/ml ciprofloxacin administered concurrently with one of two salts of prednisolone for the treatment of experimental pseudomonal keratitis. Rabbit corneas were injected intrastromally with Pseudomonas aeruginosa ATCC strain 27853. Sixteen hr after injection, rabbits were randomly divided into four treatment groups (3 rabbits, 6 eyes per group): 1) ciprofloxacin plus prednisolone acetate; 2) ciprofloxacin plus prednisolone phosphate; 3) ciprofloxacin only; 4) untreated. Signs of inflammation were graded in a masked fashion by slit lamp examination (SLE) and by estimating polymorphonuclear leukocyte (PMN) numbers in corneas 27 hr after injection. SLE scores and PMN numbers were significantly lower (P < 0.02) in eyes receiving either salt of prednisolone plus ciprofloxacin compared to the untreated controls. In contrast, SLE scores and PMN numbers were not significantly different in eyes treated with ciprofloxacin alone, compared to untreated controls (P > 0.13). No viable bacteria were recovered from any eye treated with ciprofloxacin (groups 1, 2, and 3). Ciprofloxacin concentrations in the aqueous humor of eyes in groups 1, 2, and 3 were greater than 15-fold higher than the MIC for P. aeruginosa 27853. These results suggest that either salt of prednisolone, when combined with ciprofloxacin, reduces ocular inflammation without affecting the antimicrobial efficacy of the antibiotic.

Pedia-What!

To the Editor.— Several pharmaceuticals manufactured for children have the prefix "pedia-" in their names. These include Pedicare (a line of cold and allergy preparations, McNeil), Pedialyte (oral electrolyte maintenance solution, Ross), Pediacof (a codeine-containing cough preparation, Winthrop Pharmaceuticals), PediaSure (liquid nutrition for children, Ross), Pediaflor (fluoride drops, Ross), Pediapred (prednisolone sodium phosphate, Fisons), and PediaProfen (Ibuprofen, McNeil). The first two on this list are sold without prescription. Although they are very different in appearance and therapeutic aim, I have seen some confusion among parents about these two preparations.

Assay methodology for prednisolone, prednisolone acetate and prednisolone sodium phosphate in rabbit aqueous humor and ocular physiological solutions

Prednisolone, prednisolone acetate and prednisolone sodium phosphate are glucocorticoids used for ocular, anti-inflammatory therapy. A reversed-phase high-performance liquid chromatographic assay using ultraviolet detection has been developed that affords baseline resolution of the above analytes in balanced salt solutions and rabbit aqueous humor. The drugs can be quantified at 0.025–0.05 μg/ml in the above matrices; 6α-methylprednisolone is used as the internal standard. Both esters of prednisolone are vulnerable to chemical and enzymatic hydrolysis giving prednisolone. Analysis of aqueous humor samples shows prednisolone acetate penetrating/metabolizing primarly to prednisolone; prednisolone sodium phosphate penetrates the cornea giving the ester and alcohol.

Comparative Corneal Penetration of Prednisolone Sodium Phosphate and Prednisolone Acetate in NZW Rabbits

Comparative corneal penetration studies in the literature with prednisolone sodium phosphate solution and prednisolone acetate suspension administered to rabbit eyes give conflicting results concerning the greater bioavailability of prednisolone acetate. A recent in vitro penetration study shows similar fluxes for both salt forms in terms of prednisolone, quantified by a specific HPLC assay. An in vivo comparison has been conducted in NZW rabbit eyes and shows similar bioavailability for both drugs. Prednisolone sodium phosphate, prednisolone acetate and the primary metabolite prednisolone are quantified by a specific HPLC assay in aqueous humor.

Prednisolone concentrations in cerebrospinal fluid after different prednisolone prodrugs.

The concentration-time curves of prednisolone in cerebrospinal fluid (CSF) and plasma were measured following an equimolar i.v. bolus dose of prednisolone phosphate (five patients) and prednisolone phthalate (four patients). Independent of the prodrug administered, the value of the AUC (0.360 min) in CSF was more than three times lower than the corresponding value in plasma. The AUCs of unbound prednisolone in plasma were higher after prednisolone phosphate, than after prednisolone phthalate (68.1 +/- 15.7 vs 19.0 +/- 5.2 micrograms ml-1 min, P less than 0.001). Similarly, the AUCs of prednisolone were higher in the CSF after prednisolone phosphate, than after prednisolone phthalate (17.6 +/- 2.8 vs 3.3 +/- 1.0 micrograms ml-1 min, P less than 0.0001). The results indicate that the concentrations of prednisolone in CSF are much lower than the unbound concentrations in plasma and that therapeutic inequivalence should be expected when the two prodrugs are given in equimolar doses.

Unusual deposits in the superficial corneal stroma following combined use of topical corticosteroid and beta-blocking medication

Clinical observation of eight patients with superficial stromal precipitation of calcium phosphate is presented. In all cases the predisposing factors for the formation of these depositions were: epithelial defects and the combined use of topical dexamethasone phosphate or prednisolone phosphate with topical beta-blocking agents. In two patients the medication that gave rise to these precipitates was used without preservatives, suggesting that the medication itself and not the preservatives contribute to the deposits. Discontinuance of simultaneous administration of the steroids and beta-blocking agents prevented further formation of precipitates. The authors suggest an interaction between simultaneously given steroid and beta-blocking agents, giving rise to calcium phosphate precipitates when an epithelial defect is present which allows easy access to the superficial corneal stroma.

Topical Anti-inflammatory Agents in an Animal Model of Microbial Keratitis

Topical steroids potentiate Pseudomonas keratitis in the absence of concomitant antibiotic therapy. The effects of other anti-inflammatory agents on microbial keratitis are unknown, but if these agents do not intensify the infection, they may be useful in the initial management of microbial keratitis by limiting ulceration and thus the size of the resultant corneal scar. In rabbit models of untreated Pseudomonas keratitis and pneumococcal keratitis, topical 1% prednisolone phosphate, 0.03% flurbiprofen sodium, and vehicle were applied hourly. In cases of Pseudomonas keratitis, prednisolone worsened the clinical disease, and flurbiprofen further worsened the disease. When combined with effective antibiotic therapy, neither anti-inflammatory agent worsened the disease. In pneumococcal keratitis, neither anti-inflammatory agent worsened the disease. Topical anti-inflammatory agents should be used with caution in cases of microbial keratitis at least until effective antibiotic therapy has been instituted.

A Stability Indicating HPLC Assay for Prednisolone Sodium Phosphate in Implantable Infusion Pumps

Abstract A stability indicting assay for prednisolone sodium phosphate (PSP) in solutions for implantable infusion pumps was developed. PSP and its major breakdown product, prednisolone, were separated from formulation excipients by reverse phase chromatography on a phenyl-bonded phase column using an acetonitrile-phosphate buffer mobile phase. Detection was by ultraviolet absorbance at 243 mm. Recovery from a synthetic formulation was 101.0 ± 0.4% (n=6). The method was used to monitor the stability of PSP solutions in implantable infusion pumps maintained at 37°C over a 21 day period.

Penetration of synthetic corticosteroids into human aqueous humour

The penetration of prednisolone acetate (1%) and fluorometholone alcohol (0.1%) into human aqueous humour following topical application was determined using the very sensitive and specific technique of Gas Chromatography with Mass Spectrometry (GCMS). Prednisolone acetate afforded peak mean concentrations of 669.9 ng/ml within two hours and levels of 28.6 ng/ml in aqueous humour were detected almost 24 hours post application. The peak aqueous humour level of fluorometholone was 5.1 ng/ml. The results are compared and contrasted with the absorption of dexamethasone alcohol (0.1%), betamethasone sodium phosphate (0.1%) and prednisolone sodium phosphate (0.5%) into human aqueous humour.

Topical Nonsteroidal Agents and Corneal Wound Healing

The effects on corneal wound healing of two topical nonsteroidal anti-inflammatory agents, flurbiprofen sodium (0.03%) and diclofenac sodium (0.1%), and the topical corticosteroid, prednisolone sodium phosphate (1%), were evaluated in masked, controlled rabbit studies. Healing of epithelial scrape wounds was significantly retarded in all three treatment groups for the first 3 days after wounding. There was no difference in the epithelial healing rate between the two nonsteroidal or corticosteroid treatment groups. Clinical grading of epithelial quality, conjunctival hyperemia, keratitis, stromal edema, and corneal haze were similar in all groups. There was a significant early decrease in the iritis score in the diclofenac treatment group. The strength of 2-mm central penetrating corneal trephination wounds and the collagen content of these wounds were similar in all groups. Both the topical nonsteroidal anti-inflammatory agents and the corticosteroid used in the preparations and dosages investigated in this study decreased early epithelialization of scrape wounds but had no apparent effect on corneal stromal healing. No toxic effects of the various drugs were found.

Inhibition of Blood-Aqueous Humor Barrier Breakdown With Diclofenac

Various doses of a new topical nonsteroidal anti-inflammatory agent, diclofenac sodium, were tested against prednisolone sodium phosphate in a randomized double-masked study to determine comparative efficacy and safety regarding the reduction of postsurgical ocular inflammation. Inflammation was assessed by measuring fluorescein leakage into the anterior chamber using fluorophotometry techniques. Increased leakage in each patient's operated-on eye compared with the unoperated-on control eye was attributed to a breakdown in the blood-aqueous barrier caused by the cataract surgery. Elimination or significant reduction of fluorescein leakage within a treatment group constituted increased efficacy in controlling inflammation. A total of 124 cases were analyzed. There were no preoperative differences among groups in fluorescein leakage. At 1 week after surgery, all three diclofenac groups had significantly less fluorescein leakage compared with the prednisolone group. Mean percent increases were 56% to 118% in diclofenac groups vs 324% in the prednisolone group. No differences among diclofenac concentrations were detected. The differences between prednisolone and diclofenac were also present, although of lesser magnitude, at 3 weeks. This demonstration of increased efficacy of the nonsteroidal anti-inflammatory agent vs prednisolone is promising given the known side effects of ocular steroids.

Assessment of Diclofenac on Herpes Keratitis in Rabbit Eyes

Topical diclofenac sodium is a non-steroidal anti-inflammatory drug that is being developed for use in the control of postoperative and medical inflammation. A comparison was made of 0.1% diclofenac with 1% prednisolone sodium phosphate, 0.03% flurbiprofen, and a vehicle placebo in rabbit eyes with acute herpetic keratitis in a double-masked study. Maximum corneal epithelial involvement was observed in each group on day 6 postinoculation, and in eyes subsequently treated with prednisolone, the corneal epithelial involvement appeared to be more severe and to resolve more slowly. Conjunctivitis and corneal clouding peaked on days 6 to 7 for all treatment groups and remained most severe in the placebo-treated eyes, followed closely by those treated with prednisolone. The duration of virus shedding was the same for placebo-, flurbiprofen-, and diclofenac-treated groups (50% or more were virus negative by day 10 or 11). Only prednisolone-treated eyes had an extended period of virus shedding, and the rabbit mortality rate in this group was slightly higher. It thus appears that topical diclofenac does not exacerbate acute herpes keratitis; diclofenac-treated eyes displayed less or at least no more severe disease than did the eyes treated with the other anti-inflammatory agents tested, and shedding of virus into tears was not prolonged.