Effects of topical hypotensive drugs on circadian IOP, blood pressure, and calculated diastolic ocular perfusion pressure in patients with glaucoma.
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PURPOSE: To compare the short-term effects of timolol 0.5%, brimonidine 0.2%, dorzolamide 2%, and latanoprost 0.005% on intraocular pressure (IOP), blood pressure (BP), and diastolic ocular perfusion pressure (DOPP), calculated as the difference between the diastolic blood pressure (DBP) and IOP. METHODS: According to a 4 x 4 Latin squares design for repeated measures, 27 untreated patients and patients with newly diagnosed primary open-angle glaucoma (POAG) were treated with timolol 0.5% at 8 AM and 8 PM; brimonidine 0.2% at 8 AM and 8 PM; dorzolamide 2% at 8 AM, 2 PM, and 8 PM; and latanoprost 0.005% at 8 PM. The duration of each treatment course was 6-weeks, with a 4-week washout between each treatment. IOP and BP were measured at baseline and at the end of each treatment period. IOP was measured every 2 hours throughout a 24-hour period. Sitting IOP was measured from 8 AM to 10 PM by Goldmann applanation tonometry. Supine IOP was assessed from 12 to 6 AM by means of a handheld electronic tonometer (TonoPen XL; Mentor, Norwell, MA). BP monitoring was performed by means of an automated portable device (TM-2430; A & D Co., Saitama, Japan). RESULTS: All the drugs tested decreased the IOP significantly at all time points in comparison with baseline pressure. The mean 24-hour IOP after latanoprost administration (16.62+/-0.98 mm Hg) was significantly lower than that after timolol, brimonidine, or dorzolamide (P=0.0001). During the 24-hour period, brimonidine induced a significant decrease in systolic BP (SBP) and DBP at all time points when compared with baseline measurements and with those after administration of the other drugs (P<0.0001). Timolol caused a significant decrease in DBP and SBP at all the 24-hour time points when compared with the baseline and with the dorzolamide- and latanoprost-induced changes (P<0.0001). The mean 24-hour DOPPs were 50.7+/-5.9 mm Hg at baseline, 53+/-5.5 mm Hg with timolol, 46.2+/-5.4 mm Hg with brimonidine, 55.9+/-4.6 mm Hg with dorzolamide, and 56.4+/-4.9 mm Hg with latanoprost. Brimonidine induced a significant decrease in the mean 24-hour DOPP compared with that at baseline (P<0.0001), whereas dorzolamide and latanoprost induced a significant increase (P<0.0001). CONCLUSIONS: Latanoprost seemed to induce a uniform reduction in IOP during the 24-hour period, although timolol was as effective as latanoprost during the daytime, and dorzolamide are as effective as latanoprost at night. SBP and DBP were significantly decreased by either timolol or brimonidine. In this study of patients with newly diagnosed POAG, only dorzolamide and latanoprost significantly increased mean 24-hour DOPP. (+info)
The effects of a timolol maleate gel-forming solution on normotensive beagle dogs.
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The effects of a timolol maleate gel-forming solution (TMGS) on intraocular pressure (IOP), blood pressure (BP), and pupil size (PS) were evaluated in normotensive dogs. TMGS was administered once daily to six normotensive beagle dogs. TMGS administration reduced IOP and PS. The hypotensive effect persisted for 24 hr after the administration. The mean reduction in IOP was 5.3 mm Hg (P<0.01). The changes in BP and PS were not significant. These results suggest that TMGS can potentially be used in the treatments of glaucoma and ocular hypertension in dogs. (+info)
Measurement of inflammatory cytokines by multicytokine assay in tears of patients with glaucoma topically treated with chronic drugs.
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AIM: To investigate the ocular surface inflammatory response to chronic topical treatments in patients with glaucoma by measuring the cytokine level in tears using multiplex bead analysis. METHODS: Tear samples were collected from 21 patients with glaucoma and 12 healthy volunteers. Tears were analysed for the presence of 17 cytokines: interleukin (IL)1beta, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12, IL13, IL17, granulocyte-colony stimulating factor, granulocyte-macrophage stimulating factor, interferon (INF)gamma, monocyte chemotactic protein (MCP)1, macrophage inflammatory protein 1beta and tumour necrosis factor (TNF)alpha. The cytokines in each sample of tears were measured using multiplex bead analysis with microspheres as solid support for immunoassays. RESULTS: In the tears of treated patients, proinflammatory cytokines (IL1beta, IL6, IL12, TNFalpha) were significantly increased compared with controls. T helper (Th)1 (INFgamma, IL2) and Th2 (IL5, IL10, IL4) type cytokines were also significantly higher (p<0.05); however, the most marked increase was observed with Th1 cytokines. The expression of chemokine IL8 and MCP1 was also increased in the treated group. CONCLUSION: This study shows that pro-inflammatory cytokine secretion by conjunctival cells is increased in response to topical treatments for glaucoma. The characterisation of cytokines in tears was previously limited by the small volume attainable, a limitation that has been overcome by multiplex analysis. (+info)
Effect of 2% dorzolamide on retinal blood flow: a study on juvenile primary open-angle glaucoma patients already receiving 0.5% timolol.
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AIM: To investigate whether dorzolamide modifies peripapillary retinal haemodynamics in juvenile primary open-angle glaucoma (JPOAG) patients treated with timolol. METHODS: In 40 JPOAG subjects, before and after dorzolamide coadministration with timolol, the following examinations were achieved: intraocular pressure (IOP), blood pressure (BP), ocular perfusion pressure (OPP), heart rate (HR), visual field and retinal flowmetry. RESULTS: Adjunctive therapy with dorzolamide induced the following modifications: IOP reduction [1.75 mmHg, 95% confidence interval (CI) 1.23, 2.26; P < 0.05], OPP increase (5.09 mmHg, 95% CI 2.97, 7.20; P < 0.02) and retinal blood flow improvement (35.0 arbitrary units, 95% CI 12.20, 57.80; P < 0.03). BP, HR and visual field indices did not change. CONCLUSIONS: Dorzolamide, in association or in fixed combination with timolol, significantly improves retinal blood flow in JPOAG patients. (+info)
Transport of timolol and tilisolol in rabbit corneal epithelium.
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The purpose of this study is to characterize the transport of tilisolol and timolol through the corneal epithelium, which is believed to be a tight barrier of ocular drug absorption. Cultured normal rabbit corneal epithelial cells (RCEC) were used to investigate drug transport. Primary RCEC were seeded on a filter membrane of Transwell-COL insert coated with fibronectin and grown in Dulbecco's modified Eagle's medium/nutrient mixture F-12 with various supplements. Beta-blocker permeability through the RCEC layer was measured to assess the transcellular permeability coefficient (P(transcell)) in the absence or presence of inhibitors. The transcellular permeability of tilisolol was dependent on drug concentration although timolol showed no concentration dependency. Tilisolol flux from the apical to the basal side was larger than in the opposite direction although timolol showed no direction dependency. The transcellular permeability of tilisolol from the apical to the basal side was inhibited by sodium azide, tetraethylammonium, quinidine, taurocholic acid, guanidine and carnitine. Tilisolol had an active mechanism in uptake to the corneal epithelium, probably by the organic cation transporter family, although timolol predominantly permeated via passive diffusion. This RCEC system was useful to characterize the ocular permeation mechanism of drugs. (+info)
A study of aqueous humor formation in patients with cystic fibrosis.
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The circadian pattern of aqueous formation and the effect of timolol on aqueous flow was studied in 12 patients with cystic fibrosis. Cystic fibrosis is a disease characterized by a defect in a chloride channel-associated regulatory protein found in epithelial cells. Improper regulation of these chloride channels, causes abnormal composition of exocrine secretions, including respiratory tract, gastrointestinal tract, exocrine pancreas, and sweat glands. Ocular findings previously reported include abnormal endothelial cell permeability, decreased tear secretion, and abnormal tear composition. In this study, aqueous humor flow was measured by fluorophotometry. No statistically significant difference was found when flow rates measured during the morning, during the afternoon, at night, and after topical timolol treatment were compared to normal values. The conclusion is that the beta adrenergically regulated chloride selective channels defective in patients in cystic fibrosis do not play a major role in the formation of aqueous humor or they are not regulated by the cystic fibrosis transmembrane conductance regulator (CFTR). (+info)
Timolol metabolism in human liver microsomes is mediated principally by CYP2D6.
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Timolol has mainly been used topically for the treatment of glaucoma. It has been suggested that the drug is metabolized by cytochrome P450 CYP2D6. The matter has not, however, been extensively studied. The aim here was to tentatively identify timolol metabolites and to determine the P450-associated metabolic and interaction properties of timolol in vitro. Four metabolites were identified, the most abundant being a hydroxy metabolite, M1. The K(m) value for the formation of M1 was 23.8 microM in human liver microsomes. Metabolism of timolol with recombinant P450s and correlation analysis have confirmed the conception that the drug is metabolized principally by CYP2D6, CYP2C19 being only a minor contributor (<10%) to the intrinsic microsomal clearance. The CYP2D6 inhibitor quinidine proved a potent competitive inhibitor of timolol metabolism, with an in vitro K(i) value of 0.08 microM. Fluvoxamine, an inhibitor of CYP2C19, inhibited timolol metabolism to a lesser extent, confirming its minor contribution. Timolol itself did not inhibit CYP2D6-catalyzed dextromethorphan O-demethylation. Judging from the disappearance of timolol in human liver homogenate, the in vivo half-life was extrapolated to be about 3 h, an estimate close to the half-life of about 2 to 5 h observed in vivo. In conclusion, the inhibition of timolol metabolism by quinidine should be taken into account when patients are treated with timolol. However, when plasma timolol concentrations in patients remain low (< or = 0.2 microg/l), it is suggested that such interaction is of minor clinical relevance. (+info)
Beta-adrenergic receptor blocking drugs: tear lysozyme and immunological screening for adverse reaction.
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Patients who had received long-term therapy with practolol and other beta-adrenergic receptor blocking drugs were examined ophthalmologically. Tear lysozyme concentration and serum autoantibodies (antinuclear antibodies, DNA-binding antibodies and intercellular cement substance antibodies) were measured. It was found that beta-adrenergic receptor blocking drugs may have a pharmacological effect on the lachrymal glands, but this was not associated with dry eyes or adverse reaction. Practolol was found to be capable of reducing tear lysozyme concentrations to very low levels, and this was initially associated with high titres of ICC antibody. No other drug tested produced these effects. (+info)