Biocompatibility and Pharmacokinetic Analysis of an Intracameral Polycaprolactone Drug Delivery Implant for Glaucoma.

PURPOSE: We developed polycaprolactone (PCL) implants that achieve zero-order release of a proprietary ocular hypotensive agent (DE-117) over 6 months. METHODS: The release rates of DE-117-loaded PCL devices were tuned based on an established predictive model and confirmed by in vitro release studies. Devices containing DE-117 and empty devices were implanted intracamerally in normotensive rabbits for up to 8 weeks' duration. Devices were retrieved after rabbits were euthanized and evaluated for tissue adherence. The drug remaining in each device was analyzed by high performance liquid chromatography. Drug distribution in ocular tissues was measured by liquid chromatography coupled with a tandem mass spectrometry (LC/MS/MS). RESULTS: In vitro release of DE-117 showed zero-order release with a release rate of 0.5 µg/day over 6 months. Implantation in rabbit eyes demonstrated that the devices were well tolerated in the intracameral space. Quantification of DE-117 and hDE-117 (the hydrolyzed active form of DE-117) in ocular tissues (cornea, iris-ciliary body, aqueous humor, and vitreous humor) indicated sustained release of DE-117 and its conversion to hDE-117 when released from the device. Analysis of drug remaining in the device found that concentration of hDE-117 was below the limit of detection, indicating the encapsulated drug was protected from hydrolysis in the device. CONCLUSIONS: Proof-of-concept PCL drug delivery devices containing DE-117 show promise as a long-term glaucoma treatment based on their zero-order drug release profile in vitro, biocompatibility in vivo, and effective distribution of released drug in relevant ocular tissues.

Effect of ketorolac add-on treatment on intra-ocular pressure in glaucoma patients receiving prostaglandin analogues.

BACKGROUND/AIMS: While topical ocular hypotensive agents cause secretion of endogenous prostaglandin (PG), systemic and topical non-steroidal anti-inflammatory agents inhibit its production; thus, they may interfere with therapeutic efficacy. This study aimed to investigate the effect of add-on treatment with ketorolac on intra-ocular pressure (IOP)-lowering effects of three different PG analogues. METHODS: This study included 30 adult bilateral glaucoma patients who had been receiving PG analogues for primary open-angle glaucoma (n = 25) or pseudoexfoliation glaucoma (n = 5). Ketorolac tromethamine 0.5% and placebo drops were administered to the right and left eyes of the patients, respectively, 4 times a day for 1 week. IOP measurements were performed at baseline, within the first 4 h after application, on days 1, 3 and 7, and 1 and 7 days after discontinuation of the treatment. RESULTS: Eyes receiving ketorolac had significantly lower IOP throughout the treatment period (p < 0.001). Patients who were on latanoprost, travoprost and bimatoprost did not differ with regard to the change in IOP (p = 0.780). After discontinuation, pressures became similar on day 1 (p = 0.796) and day 7 (p = 0.314). CONCLUSION: In glaucoma patients, ketorolac significantly enhances the IOP-lowering effects of latanoprost, travoprost and bimatoprost.

[Pharmaceutical and pharmacological development of antitumor prostaglandins].

Antitumor Prostaglandins such as delta 12PGJ2 and delta 7PGA1 possess a cross-conjugated dienone unit and exhibit unique antitumor effect. Lipid microshere (w/o type emulsion) was selected as pharmaceutical formulation because of physicochemical properties of prostaglandin. 13,14-Dihydro-15-deoxy-delta 7-PGA1 methyl ester (TEI-9826) were selected as a candidate for clinical trial. In a rat and mouse serum in vitro, TEI-9826 rapidly metabolized to 13,14-dihydro-15-deoxy-delta 7-PGA1 (TOK-4528), but TOK-4528 is stable as well as delta 12PGJ2. Lipid microshere containing TEI-9826 at the content of 5 mg/ml exhibited administration route and schedule dependent antitumor effect in vivo using Colon 26 bearing mouse model, which suggested that duration of serum concentration was important for antitumor effect. One of the antitumor mechanism of antitumor PG might be an induction of the cyclin-dependent kinase inhibitor p21. PPAR gamma also might be important. New type homogenizer, high pressure jet flow type homogenizer was developed in the study of antitumor prostaglandin.

Eicosanoids as a new class of ocular hypotensive agents. 3. Prostaglandin A2-1-isopropyl ester is the most potent reported hypotensive agent on feline eyes.

It has been shown that prostaglandin A2 (PGA2) is a more potent ocular hypotensive agent in cats than other PG free acids. We report here that significant IOP reduction can be achieved in normotensive cat eyes with the use of even lower doses of PGA2-1-isopropyl ester (PGA2-IE) than with PGA2, PGF2 alpha-1-isopropyl ester (PGF2 alpha-IE), or any other known ocular hypotensive agent. Furthermore, single applications of 0.5 microgram of PGA2-IE maintain significant IOP reductions for at least 24 hr. This hypotensive effect is enhanced during the first 3-5 days of daily treatment. Significant IOP reductions were maintained for several months as long as PGA2-IE was applied daily or at least once every 48 hr. None of the cats manifested signs of discomfort in response to treatment with doses ranging from 0.10 to 1.25 micrograms of PGA2-IE. Moreover, the extent of anterior chamber flare was less than that typically observed after the topical application of hypotensive doses of PGE2, PGD2, PGF2 alpha, or the esters or tromethamine salt of PGF2 alpha. Although it is possible that the human eye would respond differently to PGs of the A type, the results of these studies suggests that PGA2-IE or other esters of derived PGs of the A type, and probably the B type, may offer significant therapeutic advantages over the PGF2 alpha tromethamine salt and PGF2 alpha-IE, which have been shown to exert significant hypotensive effects on normal and glaucomatous human eyes.

Use of lipid microspheres as a drug carrier for antitumour drugs.

9-Oxo-15-hydroxy-delta 7,10,13-prostatrienoic acid methyl ester (delta 7-PGA1), an antitumour drug was incorporated into lipid microspheres of 0.2 micron diameter (lipo-delta 7-PGA1). In in-vivo experiments, lipo-delta 7-PGA1 had a significantly greater antitumour activity than free delta 7-PGA1 against P388 leukaemia. Lipo-delta 7-PGA1 slightly, but significantly, prolonged the survival time of mice inoculated with L1210 leukaemia, whereas free delta 7-PGA1 did not. Against MM46 ascites tumour, the survival time after treatment with 10 mg kg-1 of lipo-delta 7-PGA1 was significantly greater than that after the same dose of free delta 7-PGA1. The results suggest that lipid microspheres can be used as drug delivery carriers for lipid soluble antitumour agents.

Effect of indomethacin and prostaglandin A1 on renal function and plasma renin activity in alcoholic liver disease.

Renal function is known to be abnormal in patients with cirrhosis. Diminished cortical blood flow due to active renal vasoconstriction is present. Renal prostaglandins, potent vasodilators, could be released by the kidney in an attempt to maintain renal blood flow. This possibility was investigated by measuring the effect of indomethacin, an inhibitor of prostaglandin synthetase, in patients with alcoholic liver disease. Administration of indomethacin reduced the effective renal plasma flow (ERPF) and creatinine clearance by 23% and 19%, respectively (P less than 0.001), and increased serum creatinine by 29% (P less than 0.001). The response to indomethacin was variable (fall in ERPF (+)7.8% to (-)67%), but was greatest in patients with ascites. Eighty percent of ascitic patients had a greater than 15% fall in ERPF after administration of indomethacin compared with 20% of nonascitic patients (P less than 0.025). An infusion of prostaglandin A1 in 13 patients corrected the decrease in ERPF and creatinine clearance that had followed the administration of indomethacin. The administration of indomethacin caused a significant fall in plasma renin activity, 8.2 +/- 2.5 to 3.6 +/- 1.4 ng/ml/hr (P less than 0.025). The fall in plasma renin activity occurred when ERPF was depressed maximally, suggesting that endogenous prostaglandins exert more control over renin release than does ERPF. Prostaglandins appear to be an important factor in maintaining renal blood flow in patients with cirrhosis and sodium retention.

Effects of prostaglandins and their methylated analogues upon human adenylate cyclase in the upper gastrointestinal tract.

The effects of prostaglandin E2, prostaglandin A2 and their methylated analogues upon the adenylate cyclase in human gastric mucosa were studied. PG E2 and 16,16-dimethyl-PG E2 stimulated the enzyme activity to a greater degree than PG A2 and 16,16-dimethyl-PG A2. 16,16-dimethyl-PG E2 was less potent in activating the enzyme system than its parent compound. The results suggest that the more pronounced antisecretory activity of 16,16-dimethyl-PG E2 is due to its greater resistance against enzymatic degradation.