摘要:

ABSTRACTMK-422 (enalaprilat) (0.0005-0.5%) significantly reduced intraocular pressure (IOP) in African Green monkeys. Studies utilizing unilateral instillation of MK-422 and its inactive R-isomer indicated a local site of action within the eye which is dependent upon inhibition of angiotensin converting enzyme, also known as kininase II. Tonography showed a small increase (21%) in conventional aqueous humor outflow facility which did not entirely account for the IOP lowering effect of MK-422. Pretreatment with indomethacin or pilocarpine specifically attenuated the ability of MK-422 to lower IOP suggesting that biosynthesis of prostaglandins and uveoscleral outflow pathways are important in mediating the ocular hypotension. The data indicate that MK-422 may lower IOP in monkeys by virtue of its ability to prevent the breakdown of bradykinin and thereby promote the formation of endogenous prostaglandins in the eye.

ISSN:8756-3320    

DOI:10.1089/jop.1990.6.1

年代:1990

数据来源: MAL

摘要:

ABSTRACTMK-927 (dl-5,6-dihydro-4-(2-methylpropylamino)-4H-thieno(2,3b)thiopyran-2-sulfonamide-7,7-dioxide hydrochloride) is a water soluble, carbonic anhydrase inhibitor (CAI) possessing a Kiof 12.0 nM against purified human carbonic anhydrase IIin vitro. The acute instillation of one drop (50 μl) of 0.5%, 1% and 2% solutions of MK-927 maximally decreased the intraocular pressure (IOP) of ocular hypertensive, cynomolgus monkeys by 4.7, 5.9 and 9.6 mm Hg, respectively. The decline of 9.6 mm Hg represented a reduction of 27% from the corresponding vehicle-treated value of 35.3 mm Hg. Peak reductions in IOP were present at 2 to 4 hr after the instillation of the three doses and the ocular hypotensive effect was waning at 6 hr. The IOP of normotensive, monkey eyes was significantly lowered by 1% and 2% solutions of MK-927 with the effect being more transient in these eyes than in hypertensive eyes. The elevated IOP of α-chymotrypsinized rabbits was dose-dependently decreased by 0.01%, 0.1% and 0.5% solutions of MK-927. MK-927 modestly bound to rabbit ocular pigmentin vitroand the concentrations of MK-927 in the iris + ciliary body of pigmented rabbits were higher than those in the same tissue of albino rabbits after dosing with 0.5% MK-927. The ocular hypotensive effect of 2% MK-927 was greater in magnitude and longer in duration in normal pigmented than in albino rabbits. The IOP lowering action of MK-927 was local as evidenced by results of ocular distribution studies and the observation that the unilateral instillation of 0.5% MK-927 into the contralateral eye was devoid of effect on the untreated, hypertensive eye of α-chymotrypsinized rabbits. MK-927 has been selected for topical evaluation in glaucoma patien

ISSN:8756-3320    

DOI:10.1089/jop.1990.6.9

年代:1990

数据来源: MAL

摘要:

ABSTRACTEffects of D-timolol and L-timolol on IOP were compared with two rabbit models. When the drug solution was injected into vortex vein, 1% D-timolol produced ocular hypotension just like 0.5% L-timolol except D-timolol was less potent than L-timolol to lower the IOP. On the other hand, when 0.5% of D-timolol and L-timolol were instilled into the rabbit eye on IOP recovery model both agents showed equipotency to delayed the IOP recovery. Effects of D-timolol and L-timolol on ocular blood flow were also studied with two rabbit models. D-Timolol at 0.5% did not affect the ocular pulsatile blood flow measured with Langham's pneumatonometer whereas 0.5% L-timolol significantly suppressed it. D-Timolol (0.5%) was found to increase retinal and choroidal blood flows measured with laser Doppler method whereas L-timolol suppressed it. These results indicate that D-timolol though less potent than L-timolol to lower IOP, is superior over L-timolol to improve the blood flow in retina and choroid.

ISSN:8756-3320    

DOI:10.1089/jop.1990.6.23

年代:1990

数据来源: MAL

摘要:

ABSTRACTIn previous work we have determined that intracameral (IC) administration of neurotensin (NT) produces strong miosis in rabbits. However, the pharmacological mechanism of this response remains undetermined. Blockade of α and β-adrenoceptor subtypes with phenoxybenzamine and propanolol, blockade of M.muscarinic receptors with atropine or blockade of mu opioid receptors with naloxone did not affect NT-induced miosis. Of interest however was the observation that destruction of ocular dopamine (DA) nerve endings with 6-hydroxydopamine (6-OHDA) + desmethylimipramine (DMI), or blockade of D-2 DA receptors with haloperidol significantly inhibited the miotic response to IC NT.These findings indicate that an intact iridic DA pathway is required for the expression of NT-induced miosi

ISSN:8756-3320    

DOI:10.1089/jop.1990.6.31

年代:1990

数据来源: MAL

摘要:

ABSTRACTThe effect of chlorhexidine acetate on the corneal penetration of sorbitol was evaluatedin vitrousing the enucleated pigmented rabbit cornea mounted in a modified Ussing chamber. Sorbitol penetrated the cornea poorly when compared with arnolol, a beta blocker. Sorbitol penetration was improved 85% by 0.01% chlorhexidine acetate, 2.9 times by 0.1% EDTA, and 9.6 times by stripping the corneal epithelium prior to the start of the experiment. By comparison, 0.01% chlorhexidine acetate and stripping the corneal epithelium improved the corneal penetration of arnolol only 30% and 74%, respectively, whereas stripping the corneal epithelium did not affect the corneal penetration of chlorhexidine acetate. Collectively, the above findings indicate that changes in corneal integrity may dramatically affect the corneal penetration of some inert excipients in ophthalmic formulations. Such a possibility must be considered carefully in the selection of excipients.

ISSN:8756-3320    

DOI:10.1089/jop.1990.6.37

年代:1990

数据来源: MAL

摘要:

ABSTRACTPrevious studies from this laboratory have indicated that exposure of cultured bovine lens epithelial cells (BLECs) to minimal essential medium (MEM) containing 40 mM galactose (Gal) for as short a duration as 20 h results in a reduction of microsomal prostaglandin biosynthesis as demonstrated by a decrease in PGH synthase activity (Invest. Ophthalmol. Vis. Sci. 29:1452-1460, 1988). The present study shows that upon brief exposure of BLECs to Gal, the cellular content of glutathione (GSH) decreases as galactitol increases. Studies were therefore undertaken to establish whether a positive correlation existed between polyol accumulation, GSH content and the activity of PGH synthase (an enzyme known to auto-oxidize) utilizing BLECs exposed to hypergalactosemic conditions. The inhibitor of glutathione biosynthesis, L-buthionine sulfoximine (L-BSO) was used in order to lower the intracellular pool of GSH in MEM-incubated cells to a level below that routinely observed in Gal-incubated cells, under conditions whereby no galactitol accumulation had occurred. The galactitol content was 92 nmol/μg PO4in Gal-incubated cells after a 20 h exposure period; no detectable level of galactitol was observed in BLECs maintained in galactose-free MEM. L-(BSO) (1 mM) was co-administered to BLECs maintained in either MEM or Gal for 20 h. The cellular content of GSH was 1.70 ±.02 μg GSH/μg PO4in MEM alone and 0.540 ±.02 μg GSH/μg PO4in MEM+BSO. Furthermore, the GSH content in BLECs after 20 h of exposure to Gal was 0.960 ±.01 μg GSH/μg PO4but decreased to 0.110 ±.01 μg GSH/μg PO4in Gal+BSO. However, PGH synthase activity in MEM+BSO-treated BLECs was equivalent to that observed with MEM-incubated cells regardless of the significant difference in GSH content. Likewise, the addition of BSO to Gal-incubated cells, while substantially lowering the intracellular GSH content, did not further diminish the enzyme activity compared to that observed with BLECs in Gal alone. These studies demonstrate that the depletion of cellular GSH and a reduction in PGH synthase activity are uncoupled, such that a depletion in lens cell GSH does not of itself elicit a reduction of PGH synth

ISSN:8756-3320    

DOI:10.1089/jop.1990.6.43

年代:1990

数据来源: MAL

摘要:

ABSTRACTTime course and extent of strophanthin-K induced disturbances of flash electroretinogram (F-ERG) has been observed in 12 albino rabbits treated by a single dose of 1, 3 and 9 ug/0.1 ml of intravitreal injection. A phenomenon of the dependence of a- and b-wave amplitude changes on dosage was demonstrated. A 9 ug/0.1 ml dose caused a flat a- and b-wave showing the F-ERG wave could be completely suppressed by larger dose of strophanthin-K. Two parameters of "attenuation kinetics" are proposed to identify the pharmacodynamics and toxic kinetics on retina as time profile is concerned: 1) B (the slope of attenuation curve); 2) Et1/2 (half attenuative time). B and Et1/2 are helpful in making a tentative identification of the target cells on retina and in demonstrating a synergism or antagonism between drugs if any. The a-wave of F-ERG, having a steeper slope, is more sensitive than b-wave in terms of strophanthin-K toxicity bringing forth a quantitative criterion in visual pharmacology. The attenuation of amplitude in a-wave may therefore be considered as an early response to this drug. The direct pupillary response test were also done pre- and post-strophanthin-K, and the results of this test support that of F-ERG.

ISSN:8756-3320    

DOI:10.1089/jop.1990.6.51

年代:1990

数据来源: MAL

摘要:

ABSTRACTThe systemic absorption of scopolamine 0.25 % eyedrops given unilaterally was quantitated in eight patients following therapeutic drug application. Another set of eight patients received placebo drops to study the effect of scopolamine on heart rate, blood pressure and salivation. Scopolamine was rapidly and efficiently absorbed after its ocular administration. The peak plasma scopolamine concentration of 550±60 pg/ml was reached within 15 minutes in all but two patients. Ocular scopolamine did not affect patients blood pressure or heart rate when compared to patients in the placebo group. Thirty minutes after administration of scopolamine the salivary secretion was slightly but insignificantly reduced

ISSN:8756-3320    

DOI:10.1089/jop.1990.6.61

年代:1990

数据来源: MAL

摘要:

ABSTRACTIt has been found that D-timolol is equipotent or slightly less potent than L-timolol to lower the intraocular pressure (IOP) in normotensive rabbits, water loaded ocular hypertensive rabbits, α-chymotrypsin induced glaucoma rabbits, hypertonic saline infused IOP recovery model of rabbits, normotensive human volunteers, glaucoma patients and ocular hypertensive human individuals.Although L-timolol has been used widely for the treatment of glaucoma and ocular hypertension, it produces numerous side effects including cardiovascular disturbances, asthmatic attack, psychological depression, etc. Since D-timolol has much weaker affinity toward β-adrenergic receptors, it was found to have 1/80-1/300 the β-adrenergic blocking potency of L-timolol to block β-adrenergic receptors in guinea pig tracheal preparations and 1/90 of L-timolol to block β-adrenergic receptors in guinea pig atrial preparations. As a result, D-timolol showed no subjective nor objective side effects on pupil size, conjunctiva, cornea, blood pressure and pulse rate.Further, D-timolol was reported to increase retinal and choroid blood flow in rabbits without affecting overall ocular blood flow. On the contrary, L-timolol was found to significantly reduce the overall ocular blood flow and retinal and choroid blood flows in rabbits, although it might slightly increase the retinal blood flow in normotensive individuals.D-Timolol was well absorbed across the cornea as L-timolol and produced the duration of action as long as L-timolol. These results indicate that D-timolol could be a better agent than L-timolol for the treatment of glaucoma and ocular hyperten

ISSN:8756-3320    

DOI:10.1089/jop.1990.6.67

年代:1990

数据来源: MAL