Comparative study on the combined effects of bunazosin and nipradilol or timolol on intraocular pressure in normotensive rabbits.

PURPOSE: To compare the ocular hypotensive effect of nipradilol and timolol in combination with bunazosin in rabbits. METHODS: The intraocular pressure (IOP) in normal rabbits was measured using an applanation pneumatonograph. Nipradilol, timolol, and bunazosin were instilled, individually or in combination, into the inferior conjunctival sac. RESULTS: Nipradilol (0.25%), timolol (0.5%), and bunazosin (0.01%) individually lowered IOP. The IOP-lowering effects of both nipradilol and timolol were significantly enhanced by the combined application of bunazosin (0.01%). In the presence of 5% timolol or 0.1% bunazosin, IOP was further lowered by the addition of nipradilol. The IOP-lowering effect of nipradilol was partly inhibited by pretreatment with c-PTIO (10 mM), a nitric oxide (NO)-trapping agent. CONCLUSIONS: The present study demonstrated that the IOP-lowering effects of nipradilol are due to beta- and alpha1-blocking and NO-donating actions, and bunazosin has an additive effect on the IOP-lowering effect of nipradilol or timolol.

Potent reduction of intraocular pressure by nipradilol plus latanoprost in ocular hypertensive rabbits.

The present study was performed to evaluate the intraocular pressure (IOP)-lowering effect of nipradilol in combination with latanoprost on ocular normotensive and hypertensive rabbits. IOP was measured using an applanation pneumatonograph under topical application of 0.4% oxybuprocaine hydrochloride for corneal anesthesia. Ocular hypertension was induced by injection of 0.1 ml hypertonic saline (5% NaCl) into the vitreous body. Saline, nipradilol, latanoprost, sodium nitroprusside (SNP) or indomethacin was then instilled just after 5% NaCl injection. All drugs were instilled in the inferior conjunctival sac, using 50 microl drops. If more than two drugs were used, they were applied 5 min apart. Nipradilol lowered IOP in both ocular normotensive rabbits and ocular hypertensive rabbits, whereas latanoprost did not lower IOP in either. When nipradilol was applied in combination with latanoprost, the reduction in ocular hypertension was significantly enhanced, compared to the effect of nipradilol alone. A significantly potent reduction in ocular hypertension was also observed by the SNP-latanoprost combination. The IOP-lowering effects of SNP in combination with latanoprost were abolished by treatment with indomethacin. These results indicate that the IOP-lowering effect of latanoprost was enhanced when applied in combination with nipradilol or SNP, both of which have nitric oxide (NO)-donating actions. Since both combined effects were abolished by treatment with indomethacin, the mechanisms by which nipradilol combined with latanoprost lowered ocular hypertension may be related, at least in part, to the production of prostaglandins via the NO-donating action of nipradilol.

Disposition kinetics of alpha-tocopherol in apolipoprotein B knockout mice.

PURPOSE: We examined the effects of apolipoprotein B (apoB) on the disposition kinetics of alpha-tocopherol by using apoB knockout mice. METHODS: The concentrations of alpha-tocopherol in plasma and tissues were measured by gas chromatography-mass spectrometry. RESULTS: In apob (-/-) mice, the endogenous levels of alpha-tocopherol in plasma and tissues (except liver) were significantly lower, and the liver concentration was significantly higher than those in wild-type mice. After single i.v. administration of alpha-tocopherol (25 mg/kg), the area under the plasma concentration-time curve (AUC) and the distribution volume at steady state were significantly decreased, whereas the total clearance of alpha-tocopherol was significantly increased in apob (-/-) vs. wild-type mice. Alpha-Tocopherol was highly distributed to the liver, compared with other tissues. After an oral administration of alpha-tocopherol (100 mg/kg), the intestinal absorption of alpha-tocopherol was very low in apoB knockout mice, as the value of AUC0-32h for apob (-/-) mice (17.7 +/- 8.3 (microg h/mL) was significantly less than that for apob (+/+) wild-type mice (96.5 +/- 15.8 microg h/mL, mean +/- SD of five experiments, p < 0.01). The biliary excretion of alpha-tocopherol was significantly greater in apob (+/-) mice than in apob (+/+) mice. CONCLUSIONS: These results show that apoB plays a role in hepatic secretion and intestinal absorption of alpha-tocopherol.

High bioavailabilty of alpha-tocopherol loaded into poly (DL-lactic-co-glycolic acid) microspheres in apolipoprotein B knockout mice.

PURPOSE: To assess the potential clinical value of alpha-tocopherol-loaded poly (DL-lactic-co-glycolic acid) (PLGA) microspheres, we examined the disposition kinetics of alpha-tocopherol after administration of the microspheres to apolipoprotein B (apo B) knockout mice as a model of abetalipoproteinemia. METHODS: PLGA microspheres containing alpha-tocopherol were prepared by a solvent-evaporation method. The concentration of alpha-tocopherol was measured by gas chromatography-mass spectrometry. RESULTS: The mean value of particle size of alpha-tocopherol-loaded PLGA microspheres was 108 microm. The loading and the trapping efficiency of alpha-tocopherol in PLGA microspheres were 20.8% and 86.6%, respectively. When alpha-tocopherol solution (25 mg/kg) was subcutaneously administered to apob (+/+) and apob (+/-) mice, the plasma concentrations of alpha-tocopherol reached a peak at 6 h and decreased to the endogenous level within 4 days in both types of mice. However, the area under the plasma concentration-time curve (AUC) of apob (+/-) mice was significantly smaller than that in the case of apob (+/+) mice. When alpha-tocopherol-loaded PLGA microspheres (100 mg/kg) were subcutaneously administered, the plasma concentrations of alpha-tocopherol increased slowly and remained about 2-fold higher than the endogenous level at 5 to 10 days after administration in both types of mice, and there was no significant difference between the AUC values. CONCLUSIONS: The PLGA microsphere preparation of alpha-tocopherol is expected to be a very useful drug delivery system in vitamin E supplementation therapy for abetalipoproteinemia.