Dexamethasone Alcohol Research Articles

Polyhydroxyethylaspartamide-based micelles for ocular drug delivery

In this paper three copolymers of polyhydroxyethylaspartamide (PHEA), bearing in the side chains polyethylene glycol (PEG) and/or hexadecylamine (C 16) (PHEA-PEG, PHEA-PEG-C 16 and PHEA-C 16 respectively) have been studied as potential colloidal drug carriers for ocular drug delivery. The physical characterization of all three PHEA derivatives, using the Langmuir trough (LT) and micellar affinity capillary electrophoresis (MACE) techniques allowed to assume that whereas alone PHEA backbone is an inert polymer with respect to the interactions with lipid membranes and drug complexation, when PHEA chains are grafted with long alkyl chains like C 16 or in combination C 16 chains and hydrophilic chains like PEG, copolymers with lipid membrane interaction ability and drug complexation capability are obtained. In vitro permeability studies performed on primary cultured rabbit conjunctival and corneal epithelia cells, using PHEA-C 16 and PHEA-PEG-C 16 as micelle carriers for netilmicin sulphate, dexamethasone alcohol and dexamethasone phosphate, demonstrated that in all cases drug loaded PHEA-C 16 and PHEA-PEG-C 16 micelles provide a drug permeation across ocular epithelia greater than simple drug solutions or suspensions. In particular PHEA-PEG-C 16 acts as the best permeability enhancer in our experimental model. In vivo bioavailability studies conducted with PHEA-PEG-C 16 micelles loaded with dexamethasone alcohol, confirmed that this system also provides a drug bioavailability greater in comparison with that obtained with water suspension of the same drug after ocular administration to rabbits.

Penetration of topical and subconjunctival corticosteroids into human aqueous humour and its therapeutic significance

Topical and subconjunctival corticosteroids are some of the most effective and compelling treatment options in ocular inflammatory diseases. A systematic review of literature indexed by Ovid MEDLINE & EMBASE was...

Intravitreal steroids in the management of macular oedema

The use of intravitreal corticosteroids in the management of macular oedema has recently gained widespread acceptance. New long-acting steroid preparations and methods of delivery have facilitated the use of these new modalities. This review describes the various types of macular oedema for which this therapeutic option is used and the results.

The decrease of hyaluronate synthesis by anti-inflammatory steroids in vitro.

The effect of anti-inflammatory steroids (prednisolone and derivatives of hydrocortisone, dexamethasone and betamethasone) on the synthesis of hyaluronic acid and sulphated glycosaminoglycans in human skin fibroblast culture was studied. The concentrations of steroids varied between 1 x 10(-10)M and 1 x 10(-6)M. All tested steroids decreased the synthesis of hyaluronic acid to the same final level which was about 40--50% of the controls, but the concentrations required varied between different steroids. The relative inhibitory potencies of the steroids were calculated based on concentrations needed to decrease the synthesis of hyaluronate. When the inhibitory potency of hydrocortisone was calculated as one, the values of the other steroids were: prednisolone 5, hydrocortisone 17- butyrate 20, betamethasone alcohol 30, dexamethasone alcohol 38, betamethasone 17-valerate 350--400, dexamethasone monosodium phosphate and betamethasone disodium phosphate over 400. Hydrocortisone sodium succinate was as potent an inhibitor of hyaluronate synthesis as hydrocortisone alcohol. None of the tested steroids affected the synthesis of sulphated glycosaminoglycans at these concentrations. The changes ovbserved in glycosaminoglycans in the medium were in accordance with the changes in the cell layer. The possible significance of hyaluronate synthesis inhibition by anti-inflammatory steroids is discussed.

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)

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.

Collagen shield enhancement of topical dexamethasone penetration.

Collagen corneal shields were investigated as a vehicle for enhancing the ocular penetration of topical 0.1% dexamethasone alcohol in rabbit eyes. Four protocols were compared: a single dexamethasone drop, hourly drops, a 24-hour collagen shield presoaked in 0.1% dexamethasone, and a presoaked collagen shield followed by hourly drops. Dexamethasone concentrations in the cornea, aqueous, iris, and vitreous were measured by radioassay at six time intervals, and cumulative drug delivery over 6 hours was calculated for each tissue. Treatment with a presoaked collagen shield plus hourly drops resulted in peak and cumulative drug delivery to the cornea, aqueous, iris, and vitreous that was twofold to fourfold higher than delivery achieved with hourly drops alone. A presoaked shield by itself yielded equivalent or superior peak and cumulative drug delivery compared with a regimen of hourly drops. Collagen shields significantly enhance topical dexamethasone penetration and may be useful for maximizing the intraocular delivery of dexamethasone and for decreasing the required frequency of topical dexamethasone administration.

Penetration of topically applied dexamethasone alcohol into human aqueous humor.

Gas chromatography combined with mass spectrometry was used to determine the absorption of topically applied dexamethasone alcohol into the aqueous humor of human subjects undergoing routine intraocular surgery. The dexamethasone concentration in aqueous humor was greatest in the interval between 91 and 120 minutes following instillation (mean concentration, 31 ng/mL). Dexamethasone was still detectable in the aqueous 12 hours after instillation.

The pharmacokinetics of single high doses of dexamethasone in cancer patients.

We have given single high doses of dexamethasone phosphate by intravenous infusion as an antiemetic to 15 cancer patients receiving regimens containing cisplatin and/or doxorubicin. The patients received graded doses of dexamethasone phosphate, in the range 40-200 mg, dependent upon nausea and vomiting scores, during up to three consecutive cycles of cancer chemotherapy. Plasma and urine concentrations of dexamethasone (dexamethasone alcohol) were measured by HPLC. The plasma concentration - time data were described by an open two-compartment model. The pharmacokinetic variables were independent of the dose of dexamethasone over the range studied. The terminal half-time was 4.0 +/- 0.4 h and the total body clearance was 3.5 +/- 0.4 ml X min-1 X kg-1. The volume of the central compartment and the total apparent volume of distribution were 0.23 +/- 0.03 and 1.0 +/- 0.1 l X kg-1 respectively. Approximately 8% of the dose was excreted into the urine as dexamethasone.

Is there drug alternative in the treatment of massive periretinal proliferation? (author's transl)

Only a small percentage of eyes with massive periretinal proliferation (MPP) can be successfully treated by vitrectomy. This is due to the reproliferation of cells which combine to form membranes, thus causing redetachment of the retina. These filaments and membranes are formed from "fibroblast-like" cells originating from the glia cells and pigmented epithelial cells. The author attempted to produce retinal detachment by traction in 20 rabbit eyes by means of intravitreally injected homologous fibroblasts (250,000 in 0.1 ml); this was successful in 11 cases (55%). In another series with 16 rabbit eyes, 1 ml dexamethasone alcohol was administered intravitreally in addition to the fibroblast transplantation in order to inhibit fibroblast activity. This resulted in retinal detachment by traction in one case only (6%). Hence the number of detachments by traction was significantly lower with eyes with additional intravitreal administration of dexamethasone.

Glucocorticosteroid Inhibition of Intraocular Proliferation After Injury

Perforating injuries were produced in the posterior segment of rabbit eyes. We studied the inhibitory effect of a slowly water-soluble corticosteroid, dexamethasone alcohol, on fibroblast growth. The treated group received a single intravitreal injection of 1 mg of the corticosteroid. The eyes were observed for four weeks. Transvitreal proliferation was significantly decreased and wound healing was delayed as compared to a control group. Inhibition of intraocular proliferation by high doses of intravitreally injected corticosteroid may be useful in the treatment of eyes with penetrating and perforating injuries.

Inhibition of Intraocular Proliferations with Intravitreal Corticosteriods

Autotransplantation of one fourth million tissue cultured fibroblasts from rabbit rump skin into the vitreous cavity resulted in intravitreal strand formation and traction retinal detachment (27 of 47 eyes, 57%). A single intravitreal injection of 1 mg of dexamethasone alcohol inhibited fibroblast growth as judged by the significantly reduced number of retinal detachments (11 of 46 eyes, 24%). Retinal neovascularization that was observed when fibrous strands came into contact with vascularized retina (nine of 47 eyes, 19%) was also inhibited after corticosteroid application (two of 46 eyes, 4%).

Disposition of synethetic glucocorticoids. I. Pharmacokinetics of dexamethasone in healthy adults.

The pharmacokinetics of dexamethasone alcohol is described in six male and six female healthy adult volunteers who each received 8 mg of dexamethasone phosphate by bolus intravenous injection. Quantitation of the alcohol was done using a high-performance liquid chromatographic method with improved specificity. Statistical evaluation of the results generated by nonlinear least-squares regression analysis of the plasma concentration-time data shows that the phosphate ester is very rapidly hydrolyzed to the alcohol and a biexponential equation is the simplest polyexponential equation that is consistent with the data. The terminal phase half-life t1/2 beta was significantly greater (P less than 0.05) in males (mean 201.5 min) than in females (mean 142.3 min). They prolonged t1/2 beta in males did not appear to be caused by an impaired capacity to eliminate dexamethasone since the total plasma clearance did not differ between males (mean 24.5 ml/min) and females (mean 242.9 ml/min). There was, however, a high positive correlation between t1/2 beta and Vdss among the 12 adults (r = 0.92, p less than 0.001). There were also significant correlation between Vdss and body weight (r = 0.67, p less than 0.05) and t1/2 beta and body weight (r = 0.80, p less than 0.01). The difference in body weight between the sexes seems to be the main factor contributing to the difference observed in t1/2 beta. An average of only 2.6% of the dose was found unchanged in a 24-hr urine sample, and hence it appears that dexamethasone is primarily eliminated by extrarenal, probably hepatic, mechanisms.

Comparative toxicity of two-dexamathasone derivatives following topical ocular instillation to rabbits II. Systemic histopathological changes

Dexamethasone-21-tertiary butyl acetate (dexamethasone TBA) and dexamethasone alcohol at concentrations of 0.2, 0.1, 0.01, and 0.001% were topically instilled into the right eyes of groups of 10 rabbits for 21 consecutive days. Vehicle control and untreated control were used for comparative evaluation. The dose-dependent chages for each compound were ( 1) lipid and glycogen infiltration of liver, ( 2) hydropic changes of liver ( 3) vacuolation and multifocal hepatic necrosis of liver, ( 4) atrophy of Peyer's patches of intestines, ( 5) white pulp atrophy of the spleen and ( 6) atrophy of the adrenal cortex. No pathological changes were noted for other tissues including the eye. In conclusion, the results indicate that systemic histopathologic changes for both steroids were comparable and typical for steroids.

Topically applied steroids in corneal disease. V. Dexamethasone alcohol.

Topical application of a commercially available aqueous suspension of dexamethasone alcohol, 0.1%, produced measurable quantities of the steroid in both the cornea and in the aqueous humor under all three experimental ocular conditions studied. Drug bioavailability was greatest after removal of the corneal epithelium, but the alcohol derivative of dexamethasone also penetrates through the intact corneal epithelium. Comparison of our present findings with previous experimental data from this laboratory confirms the superiority of an aqueous vehicle over petrolatum ointment for delivering dexamethasone to the eye.