Search

PURPOSE To determine and compare the daily cost of various glaucoma medications in China. MATERIALS AND METHODS The majority of glaucoma medications commercially available in China were included in this research. The total number of drops in 1 bottle of each medication was counted drop by drop. The mean volume per bottle of each medication was calculated. The cost per drop, number of days for both eyes usage per bottle, and daily cost was calculated. RESULTS (1) The volume per drop ranged from 0.03 mL (brinzolamide 1%, travoprost 0.004%, bimatoprost 0.03%, and latanoprost 0.005%) to 0.05 mL (timolol 0.5%-Chengrui and pilocarpine 0.5% and 2%-Zhenrui). (2) The cost per bottle ranged from $0.69 (US dollar) (timolol 0.5%-Malaisuan Saimaluo'er) to $40.78 (latanoprost 0.005%). (3) The number of days for both eyes usage per bottle ranged from 52 days (bimatoprost 0.03%) to 11 days (pilocarpine nitrate 0.5%-Zhenrui). (4) The daily cost for both eyes usage from expensive to cheap were latanoprost 0.005%-$0.91, travoprost 0.004%-$0.77, brimonidine 0.2%-$0.61, bimatoprost 0.03%-$0.46, D-timolol 1%-$0.36, brinzolamide 1%-$0.34, pilocarpine 2%-Zhenrui-$0.28, levobunolol 0.5%-$0.25, betaxolol 0.25%-$0.24, pilocarpine 0.5%-Zhenrui-$0.18, pilocarpine 2%-Huming-$0.16, carteolol 1%-Mikelan-$0.15, carteolol 2%-Mikelan-$0.15, pilocarpine 1%-Huming-$0.10, timolol 0.5%-Chengrui-$0.08, timolol 0.5%-Malaisuan Saimaluo'er-$0.03. CONCLUSIONS The daily cost of glaucoma medications in China ranged much more wildly than developed countries. These data may be useful in selecting medications for glaucoma therapy. The ophthalmic solution of prostaglandins is powerful in reducing intraocular pressure. However, its high price should be considered when selecting glaucoma medications in China.

Most ocular solutions enter the eye through the corneal epithelial barrier. In order to pass through this barrier, these hydrosoluble drugs require to be associated with a detergent agent to increase topical efficiency. Although these agents have a preservative action, it was recently demonstrated that, after short or long term use, toxic side effects on the ocular surface will occur.

To compare the ocular hypotensive activity and safety profile of long-acting 1% carteolol hydrochloride eye drops (long-acting formulation) to those of 1% carteolol hydrochloride eye drops(currently prescribed drug) for reduction of intraocular pressure.Patients with primary open-angle glaucoma or ocular hypertension (146 cases) were assigned randomly to the long-acting drug group (74 cases) and the currently-prescribed drug group (72 cases). Long-acting eye drops were instilled once a day in the morning (along with one drop of placebo at night), and currently-prescribed eye drops were instilled twice a day in the morning and at night. Eye drops were administered for 8 weeks. Intraocular pressure was monitored at 2, 4, and 8 weeks after the initiation of drug instillation for evaluation of equivalence.Intraocular pressure was significantly reduced during the entire follow-up period in both groups. In the long-acting drug group, the reduction of intraocular pressure was--3.5 +/- 0.2,--4.3 +/- 0.2 and--4.6 +/- 0.3 mmHg at 2, 4, and 8 weeks, respectively (paired t test). In the currently-prescribed drug group, the reduction of intraocular pressure was--4.1 +/- 0.2,--4.4 +/- 0.3 and--4.6 +/- 0.2 mmHg at 2, 4, and 8 weeks(paired t test). The safety profile was similar in both groups, and the tolerance for the long-acting eye drops was as good as for the currently-prescribed eye drops.Because the efficacy of both drugs was equivalent, with an identical safety profile, the long-acting eye drops seem to be an efficacious formulation for clinical use in Japanese glaucoma patients.

Ocular carteolol (Mikelan), Teoptic, Ocupress) is a nonselective beta-adrenoceptor antagonist with intrinsic sympathomimetic activity (ISA). Ocular carteolol effectively reduces intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) or ocular hypertension (OH). Twice-daily administration of standard carteolol has generally similar IOP-lowering efficacy to other ocular beta-adrenoceptor antagonists such as timolol, betaxolol and metipranolol in patients with OAG or OH. In addition, long-term treatment with carteolol has similar efficacy to timolol and betaxolol in terms of reducing IOP and maintaining visual fields in patients with newly diagnosed primary OAG (POAG). The new long-acting formulation of once-daily carteolol has equivalent efficacy to the standard formulation of carteolol administered twice daily in patients with OAG or OH. Both the standard and long-acting formulations of ocular carteolol are generally well tolerated in terms of topical adverse effects involving the eyes or systemic adverse effects involving the cardiovascular system. Thus, twice-daily carteolol is a well established option in the treatment of glaucoma and OH, and the new once-daily formulation of long-acting carteolol offers similar efficacy and tolerability with a potential for improved patient adherence.

International audience; 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)1β, IL2, IL4, IL5, IL6, IL7, IL8, IL10, IL12, IL13, IL17, granulocyte‐colony stimulating factor, granulocyte‐macrophage stimulating factor, interferon (INF)γ, monocyte chemotactic protein (MCP)1, macrophage inflammatory protein 1β and tumour necrosis factor (TNF)α. 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 (IL1β, IL6, IL12, TNFα) were significantly increased compared with controls. T helper (Th)1 (INFγ, IL2) and Th2 (IL5, IL10, IL4) type cytokines were also significantly higher (p

To compare the additive effect of dorzolamide or carteolol to latanoprost on intraocular pressure (IOP) in glaucoma patients.Prospective open-label randomized crossover clinical study.A total of 64 patients with primary open-angle glaucoma were treated with latanoprost 0.005% once daily for 3 months then randomized to receive latanoprost plus dorzolamide 1% 3 times daily (dorzolamide preceding group; n=32) or carteolol hydrochloride 2% twice daily (carteolol preceding group; n=32) for a further 3 months. Then, all patients were crossed over to the opposite treatment arm for a further 3 months. IOP was recorded each month at around the time same as on the baseline day.Sixty-one patients (95%) completed this trial. In the dorzolamide preceding group, mean (+/-SD) IOP was 19.0+/-2.1 mm Hg at baseline and 16.0+/-2.1 mm Hg at the end of latanoprost monotherapy (P0.01). Addition of dorzolamide reduced IOP to 15.0+/-1.3 mm Hg and this was not changed by switching to carteolol (15.1+/-1.7 mm Hg). In the carteolol preceding group, IOP was 19.1+/-1.9 mm Hg at baseline and 16.2+/-1.2 mm Hg at the end of latanoprost monotherapy (P0.01). Addition of carteolol reduced IOP to 14.9+/-1.5 mm Hg, and after switching to dorzolamide IOP was 15.2+/-1.5 mm Hg. Mean additional IOP reduction was 0.9+/-1.2 mm Hg (5.6%) for the latanoprost-dorzolamide combination and 1.1+/-1.5 mm Hg (6.8%) for the latanoprost-carteolol combination. Hence, IOP reduction by carteolol and dorzolamide additionally to latanoprost was not different.Both dorzolamide and carteolol reduce IOP additively when used in combination with latanoprost, and the additive effect of these drugs is equal.

It is necessary to decrease topical anti-glaucoma medication for severe glaucoma with pseudopemphigoid caused by anti-glaucoma eye drops. Glaucoma filtrating surgery is often needed instead of medication, but the prognosis is poor because it induces scar fomation and makes the filtrating bleb vanish.An 85-year-old male patient with exfoliation syndrome had twice undergone glaucoma surgery about ten years previously. His intra-ocular pressure (IOP) was high despite topical anti-glaucoma medication. At the first examination in our hospital, he had severe superficial punctate keratopathy, blephariticshortening and symblepharon, and we therefore diagnosed severe pseudopemphigoid induced by anti-glaucoma eye drops. Because his IOP could not be controlled by topical and general medication, we conducted a glaucoma filtrating operation using amniotic membrane.The administration of oral anti-inflammatory drugs before and after surgery and the use of amniotic membrane prevented post-operative scar formation and the progress of symblepharon, resulting in the successful control of IOP after surgery.

The purpose of this study was to investigate the effects of various antiglaucoma drugs, including timolol, betaxolol, carteolol, levobunolol, dipivefrin, and pilocarpine, on cellular proliferation in cultured human corneal keratocytes. Human corneal keratocytes were cultured with RPMI-1640 medium containing 10% fetal bovine serum. Antiglaucoma drugs were prepared from original concentrations to dilutions of 1/10, 1/100, and 1/1,000. After exposure to drugs for 100 minutes, cellular proliferation was estimated by [3H] thymidine uptake methodology. It was found that cellular proliferation in corneal keratocytes was inhibited by only a 1/10 dilution of various drugs including timolol, betaxolol, carteolol, levobunolol, dipivefrin, and pilocarpine. The [3H]thymidine uptake values were significantly inhibited to 63%, 18%, 87%, 68%, 55%, and 67% by a 1/10 dilution of the above drugs. However, the cellular proliferation was also significantly suppressed by 0.01 mg/mL of benzalkonium chloride preservative. It is shown that the inhibition of cellular proliferation by high concentrations of antiglaucoma drugs may result from the benzalkonium chloride preservative contained in these drugs.

To compare the effects of nipradilol and carteolol on intraocular pressure (IOP) when added to latanoprost treatment for glaucoma patients.Fifty patients with primary open-angle glaucoma were treated with latanoprost 0.005% once daily for 3 months. Then they were assigned to one of two groups randomly. One group received nipradilol 0.25% twice daily (nipradilol preceding group; n = 25), and the other carteolol hydrochloride 2% twice daily (carteolol preceding group; n = 25), for 3 months in addition to latanoprost. Then, nipradilol and carteolol were switched, and the subjects were treated for 3 more months. One eye was selected randomly for analysis.In the nipradilol preceding group, IOP was 21.4 +/- 2.3 mmHg (mean +/- SD) at baseline, and 16.8 +/- 1.9 mmHg at the end of latanoprost monotherapy (P0.01). The addition of nipradilol decreased IOP to 15.8 +/- 1.7 mmHg, and the change to carteolol, to 15.3 +/- 2.0 mmHg. In the carteolol preceding group, IOP was 21.2 +/- 2.0 mmHg at baseline, and 17.0 +/- 2.1 mmHg at the end of latanoprost monotherapy (P0.01). The addition of carteolol decreased IOP to 15.4 +/- 1.8 mmHg, and the change to nipradilol, to 16.3 +/- 1.9 mmHg. Additional IOP reduction was greater with carteolol than with nipradilol (cross-over analysis of variance; P = 0.0005).Both nipradilol and carteolol have additive effects when used in combination with latanoprost. Carteolol, however, may have a more potent effect than nipradilol.

The present study was designed to verify our previous hypothesis that carteolol, a beta1/beta2-adrenoceptor-blocking agent, is a nonconventional partial agonist of cardiac beta1-adrenoceptors. To this purpose, we characterized the effects of carteolol in guinea pig myocardial preparations and measured the affinities of carteolol for high- and low-affinity sites of beta1-adrenoceptors labeled by CGP12177 [(-)4-(3-t-butylamino-2-hydroxypropoxy)-2-benzimidazol-2-one]. All experiments were performed in comparison with xamoterol, a cardioselective beta1-adrenoceptor partial agonist. Both drugs caused cAMP-dependent positive inotropic and chronotropic effects, but carteolol was less effective and less potent than xamoterol, and its cardiac actions were not affected by conventional concentrations of the beta-blocker propranolol. Both carteolol and xamoterol antagonized the cardiac effects of isoprenaline, but although the antagonistic concentrations of xamoterol were almost equal to those producing cardiostimulation, the antagonistic concentrations of carteolol were 3 log units lower than those causing cardiostimulant effects. Both carteolol and xamoterol competed with (-)[3H]CGP12177 for a high-affinity site of beta1-adrenoceptors, but carteolol showed a higher affinity than xamoterol. Moreover, carteolol, unlike xamoterol, bound also to a low-affinity site of the receptors. The binding affinity constants of the drugs for the high-affinity site correlated well with the respective blocking potencies against isoprenaline, whereas the affinity constant of carteolol for the low-affinity site was well related to its agonist potency. In conclusion, our findings demonstrate that carteolol, unlike xamoterol, is a nonconventional partial agonist, which causes agonistic effects through interaction with the low-affinity propranolol-resistant site of beta1-adrenoceptors and antagonistic actions through the high-affinity site of the same receptors.

We investigated whether carteolol hydrochloride, which has intrinsic sympathomimetic activity (ISA), inhibits the production of proinflammatory cytokines using mouse macrophages (MPs) and peripheral-blood mononuclear cells (PBMCs). MPs and PBMCs were collected from BALB/C strain mice, treated simultaneously with lipopolysaccharide (LPS) and test agents (carteolol hydrochloride, timolol maleate, betaxolol hydrochloride, levobunolol hydrochloride, or nipradilol) in medium, and incubated in a CO2 incubator. TNF-alpha and IL-6 in medium were measured by ELISA. Carteolol hydrochloride significantly inhibited the production of TNF-alpha and IL-6 by MPs at 10(-5) M and higher (p0.01) or PBMCs at 10(-6) M and higher (p0.01) compared to the controls, while the other test agents had no inhibitory effect. Carteolol hydrochloride inhibited the production of proinflammatory cytokines by inflammatory cells, raising the possibility that this intraocular hypotensive drug may be expected to have anti-inflammatory effects in patients with increased intraocular tension and postoperative inflammation.

Purpose To evaluate the ocular factors contributing to keratoepitheliopathy in glaucoma patients treated with or without anti-glaucomatous eyedrops, and the influences of each anti-glaucomatous eyedrop to keratoepitheliopathy. Methods The presence and severity of keratoepitheliopathy was investigated in 193 eyes of 110 glaucoma patients. The ocular factors examined were the status of the lipid layer of the tear fluid as assessed by a specular reflection video-recording system, tear volume assessed by Schirmer's test, and tear film stability assessed by tear break-up time. The influences of combined anti-glaucomatous eyedrops and each anti-glaucomatous eyedrops to keratoepitheliopathy were investigated. Results The overall occurrence of superficial punctate keratitis was 29.0%. Superficial punctate keratitis was more frequently observed in patients who used more than two anti-glaucomatous eyedrops (35.9%) than in those who used without (19.7%) and one (30.9%). Results of Schirmer's test and break-up time were worse in patients who used combined medication. The occurrence of superficial punctate keratitis in patients who used timolol (46.2%) was significantly more frequent than in those who used carteolol (4.2%). Severity of superficial punctate keratitis and break-up time in patients who used timolol were significantly worse than in those who used carteolol. There were no differences of keratoepitheliopathy and ocular factors between patients who used latanoprost and unoprostone. Conclusion The usage of multiple anti-glaucomatous eyedrops induces keratoepitheliopathy by reducing the tear volume and the tear film stability. Carteolol may be used more safely for corneal epithelium.

Antiglaucoma drugs have been associated with conjunctival and trabecular inflammatory cell infiltrates. However, the underlying mechanisms are still poorly understood. The aim of this study was to assess the effects of antiglaucoma medications on the complement system, an early mediator of the inflammatory response.Human serum was first treated with a classical or alternative pathway activator (aggregated human IgG or zymosan, respectively) in the presence or the absence of preservative-free or benzalkonium (BAK)-preserved antiglaucoma drugs. CH50 assay was then performed to assess the functional activity of residual complement in treated serum.In the absence of complement activator, the antiglaucoma drugs tested in this study were all devoid of intrinsic complement-activating potency. Preserved and preservative-free carteolol as well as preserved latanoprost did not worsen or prevent complement activation induced by zymosan or aggregated IgG. Unexpectedly, both preserved and unpreserved timolol and betaxolol significantly counteracted the effects of complement activators. Timolol prevented activation triggered by both IgG and zymosan to the same extent (24% to 29%), despite the presence of BAK in the preserved formulation. Betaxolol was twice as effective at preventing the effect of IgG (34% to 37%) than that of zymosan (14%), regardless of the presence of BAK. However, BAK itself strongly aggravated complement activation by both activators.Carteolol, timolol, betaxolol and latanoprost did not activate complement system. On the contrary, the beta-blockers timolol and betaxolol exerted an anti-inflammatory effect by preventing complement activation. The deleterious effect of benzalkonium seems to have been neutralized within the preserved eyedrops through a mechanism that remains to be elucidated. Our study suggests that inflammatory signs in glaucoma patients should not be attributed to complement activation by antiglaucoma drugs.

The effects of beta-blocking agents on exercise tolerance in cardiopulmonary exercise testing (CPX) have not been fully identified. Because the negative chronotropic effects of these agents produce a sluggish increase in heart rate (HR) during CPX, exercise capacity is actually underestimated by methods that depend on HR-related variables such as peak oxygen uptake (O(2)) and anaerobic threshold (AT). The aim of this study was to clarify the efficacy of beta-blocking agents by means of O(2) kinetics, a parameter independent of HR, in patients with dilated cardiomyopathy (DCM).The exercise capacity of 12 patients (9 men and 3 women; mean +/- SD age, 54 +/- 12 years; New York Heart Association class I [n = 1], NYHA class 2 [n = 4], and NYHA class III [n = 6]) with DCM, who were treated with beta-blocking agents, was evaluated by CPX. O(2) was calculated from respiratory gas analysis on a breath-by-breath basis. Nine patients were treated with metoprolol (30 mg or 60 mg), two with carteolol (10 mg or 20 mg), and one patient with atenolol (25 mg).All patients showed a significantly favorable results (ie, improvement in symptoms of congestive heart failure). Peak O(2) (20.4 +/- 5.1 to 18.8 +/- 5.8 mL/min/kg), AT (12.7 +/- 3.5 to 12.1 +/- 2.1 mL/min/kg), and exercise time (4.8 +/- 2.2 to 4.5 +/- 2.1 s) were unchanged. The time constant of O(2) kinetics (tau) on response to constant low-dose work loading (warm up) decreased significantly (64 +/- 30 to 44 +/- 24 s; p0.01) and ejection fraction increased (30 +/- 14 to 44 +/- 15%, p0.01) significantly following treatment with beta-blocking agents. In spite of excluding two NYHA I patients, these changes were also statistically correlated.In the low level of exercise, tau was prolonged in patients with DCM. Although indexes of total exercise time and AT were not useful markers for clinical improvement in cardiac performance as assessed by echocardiography, measuring can validly assess the beneficial effects in heart failure treated with beta-blocking agents.

A new rapid and sensitive high-performance liquid chromatography (HPLC) method has been developed for the simultaneous identification and quantification in human plasma of the 13 most commonly prescribed beta-blockers and one active metabolite-atenolol, sotalol, diacetolol, carteolol, nadolol, pindolol, acebutolol, metoprolol, celiprolol, oxprenolol, labetalol, propranolol, tertatolol and betaxolol. It involves liquid-liquid extraction procedures followed by liquid chromatography coupled to photodiode-array UV detection with a fixed wavelength at 220 nm for quantification. Compounds were separated on a 5 microm Hypurity C(18) (ThermoHypersil) analytical column (250 mm x 4.6 mm, i.d.) using a gradient of acetonitrile-phosphate buffer pH 3.8 at a flow rate of 1.0 ml/min. The total analysis time was 26 min per sample. Extraction recoveries were between 74 and 113% for the polar compounds and between 20 and 56% for the most apolar compounds. Calibration lines were linear in the range from 25 to 1000 ng/ml for all compounds excepted carteolol and nadolol (50-1000 ng/ml), all of them with coefficients of determination (r2 values) >/=0.994. Limits of detection (LODs) ranged from 5 to 10 ng/ml. Intra-assay and inter-assay precision and accuracy were studied at two concentration levels (100 and 500 ng/ml). The intra-assay coefficients of variation (CVs) for all compounds were

Carteolol is a beta-adrenoceptor antagonist with intrinsic sympathomimetic activity. Used topically to reduce intraocular pressure, it is typically applied twice daily. In an effort to provide a once-daily dosing regimen, carteolol was formulated with 1% alginic acid. Sodium alginate is a natural polymer product with bioadhesive properties providing increased corneal contact time and a better carteolol penetration through the cornea. The objective of this study was to evaluate the efficacy and safety of long-acting 1% carteolol alginate solution compared to standard 1% carteolol solution.This was a double-masked, parallel group, multicentre study. Patients with ocular hypertension or open angle glaucoma (n=151) were randomly assigned to receive either 1% carteolol alginate once daily (AM) or standard 1% carteolol solution twice daily for 2 months. The masking was maintained through the use of a placebo in the evening for the alginate group. Entry into the study required unmedicated intraocular pressure (IOP) between 23 mmHg and 32 mmHg at 9 AM and 11 AM. Patients using ocular hypotensive medication were required to undergo a washout. All patients provided written informed consent. Excluded from the study were patients with angle closure, congenital, secondary glaucoma or advanced glaucoma; any intraocular infection or inflammation, ocular trauma, ocular surgery or laser trabeculoplasty within the previous 3 months; contraindications to the use of beta adrenoceptor antagonists; systemic medications likely to modify IOP prescribed or modified during the previous 3 months; ocular steroid use; contact lens wear; and pregnant and lactating women. Patients were evaluated at baseline, 15 and 60 days, with IOP measurements at 9 AM and 11 AM. At day 15 and day 60, IOP was measured just before instillation of medication (9 AM) and 2 hours after (11 AM). Slit lamp examinations were performed at each follow-up examination, together with measurement of heart rate and blood pressure (10 AM) and ocular tolerance after medication (11 AM). The primary efficacy criterion was the decrease in IOP from baseline at day 60 for each measurement at 9 AM and 11 AM. The study eye was the eye with the higher IOP at day 0 or, if equal, the right eye.Efficacy-of the 151 patients included in the study, 149 were evaluated (two patients were lost to follow-up after day 0): 74 in the alginate group and 75 in the standard group. Both treatment groups were comparable at day 0 except for sex, diastolic blood pressure, and IOP in the fellow eye. At 09.00 hours (presumed trough) on day 60, mean reductions from baseline in intraocular pressure were 6.32+/-2.87 and 5.67+/-3.30 mmHg for the alginate carteolol and standard groups, respectively. At 11.00 hours (presumed peak), mean reductions were 6.70+/-2.81 and 6.55+/-3.35 mmHg, respectively. At each evaluation time, the two unilateral t tests were highly significant (p0.005), confirming the equivalence of both treatments. Conclusions were not modified taking into account sex and diastolic blood pressure. Safety- Slight decreases in heart rate and blood pressure means were observed in both groups at follow-up visits with no significant difference between groups. Subjective tolerance upon instillation was judged good or very good at day 60 by 100% of alginate patients and by 98.7% of standard patients. Transient discomfort (mainly stinging or burning sensation) was reported by approximately 4% - 6% of patients in each treatment group at each visit. A blurred vision sensation was reported by 2 out of 74 patients of the alginate group. Among the 17 reported adverse events, three were assessed as drug-related: one vertigo, one superficial punctate keratitis in the alginate group and one decrease in blood pressure in the standard group. No serious adverse events were reported.The new alginate formulation of long-acting carteolol 1% given once daily is as effective as standard 1% carteolol given twice daily, with no meaningful differences regarding safety. This efficacy wasy was verified at 9 AM (24 hours after the last drop of long-acting carteolol or 12 hours after that of standard carteolol) and at 11 AM (2 hours after the morning drop). The new alginate formulation of long-acting carteolol 1% given once a day is effective and well tolerated by glaucoma patients who require chronic treatment.

PURPOSE. To report a case of corneal neovascularization possibly associated with latanoprost therapy. METHODS. Case report: A 67-year-old man developed a progressive stromal corneal neovascularization in his right eye within eight months of a corneal trauma. At admission, he was receiving latanoprost 0.005% therapy. His topical medications were rearranged: latanoprost was replaced with carteolol hydrochloride 1% twice daily bilaterally and prednisolone acetate 1% was added twice daily in the right eye. RESULTS. One month later, he presented regression of the corneal neovascularization and an increase in visual acuity. CONCLUSIONS. Latanoprost, an arachidonic acid derivative, could have directly or indirectly stimulated the corneal neovascularization in this patient with a history of nonpenetrating corneal trauma.

Purpose To evaluate the potential of topical iganidipine ophthalmic solution to exert Ca(2+)-antagonistic activity in the posterior parts of the eye without inducing systemic effects, ocular and periocular penetration of topically instilled iganidipine was studied in pigmented rabbits. Method First, (14)C-iganidipine solution (0.03%, 30 microL) was instilled into one eye, and vehicle into the other eye to determine the intraocular penetration of iganidipine and to measure the radioactivity of ocular tissues 0.25, 0.5, 1, 2, 4, and 12 hours after a single instillation (n = 3, respectively). Second, iganidipine (0.03%) or betaxolol (0.5%) was unilaterally instilled twice daily for 20 days to study the effects on intravitreously injected various doses of endothelin (ET)-1-induced retinal artery constriction to evaluate whether a pharmacologically active level of the drug penetrated to the posterior retina and to estimate the drug level in the posterior retina (n = 6, respectively). Third, iganidipine (0, 10, or 30 microg/kg: n = 6, 3, and 6, respectively) was intravenously injected to study the effects on intravitreously injected ET-1-induced retinal artery constriction to evaluate iganidipine levels in the posterior retina. Fourth, periocular penetration of iganidipine was studied by means of whole-head autoradiography after a single instillation of (14)C-iganidipine (0.09%, 30 microL; n = 5). Results Penetration of topically applied iganidipine to the cornea or aqueous humor was high and estimated to be at least 10 times higher than that reported for timolol or carteolol. Concentrations in the iris-ciliary body or retina-choroid were much higher than in the plasma, both in the treated and control eyes, suggesting that iganidipine binds to uveal pigments. Twice-daily 20-day instillation of iganidipine (0.03%), but not of betaxolol (0.5%), significantly suppressed constriction of the retinal arteries induced by intravitreous injection of ET-1 at a dose of 2.5 or 0.5 ng in the ipsilateral eye. Intravenous injection of iganidipine at a dose of 30 microg/kg (giving a free plasma concentration of approximately 10(-8) M), but not at a dose of 10 microg/kg, significantly suppressed intravitreous ET-1-induced (0.5 ng) constriction of the retinal artery to a similar degree as twice-daily 20-day instillation of 0.03% iganidipine. After a single instillation of 0.09% iganidipine, the equivalent concentration of iganidipine in the ipsilateral retrobulbar periocular space estimated from autoradiography was approximately 3.9 x 10(-8) M between 15 minutes and 1 hour after instillation, consistently higher than in the untreated contralateral eyes by approximately 3.0 x 10(-8) M (P = 0.043). Conclusions In rabbits, topically instilled iganidipine, a Ca(2+) antagonist, in a 0.03% solution reaches the ipsilateral posterior retina or retrobulbar periocular space by local penetration at concentrations sufficient to act as a Ca(2+) antagonist.

The cornea is a major pathway for drug delivery to diseased eye structures. We have investigated the application of 1-s bursts of 20-kHz ultrasound, at I(SAPA) of 14 W/cm(2) (I(SATA) of 2 W/cm(2)), for enhancement of corneal permeability to glaucoma drugs of different lipophilicity (atenolol, carteolol, timolol and betaxolol). The permeability of rabbit cornea increased by 2.6 times for atenolol, 2.8 for carteolol, 1.9 for timolol and 4.4 times for betaxolol (all p-values < 0.05), after 60 min of ultrasound (US) exposure in vitro. The differences between the treatment and control experiments were statistically significant after 10 to 30 min of US exposure for all four drugs. US application appeared to produce epithelial disorganization and structural changes in the corneal stroma. Further studies are needed to determine the optimal US parameters for a safe and effective treatment.

βBlockers lower intraocular pressure (IOP) by reducing the rate of aqueous inflow.1 Shortly after the commercial release of topical timolol maleate in 1978 it became the most widely used ocular hypotensive agent. Its potency, combined with its twice daily frequency of instillation and lack of induction of miosis or accommodative spasm, was seen as a major advantage.2 Timolol was considered a revolutionary advance in the medical management of glaucoma. In Australia, only laevobunolol later provided an alternative to timolol as a non-selective β blocker, and in 1995 betaxolol hydrochloride offered the choice of a relatively selective β1 blocker. Betaxolol has been demonstrated to have a wider safety margin than the non-selective agents, particularly for the cardiovascular and respiratory systems.3 It is less likely than timolol to provoke bradyarrhythmias, heart block, and bronchoconstriction. It is also somewhat less effective as an ocular hypotensive agent.4 In the laboratory, betaxolol has been found to have calcium channel blocking effects independent of its β blocking properties,5 and this has led to speculation that it may be useful not only in IOP reduction, but also as an inhibitor of episodic vasoconstriction in the optic nerve head region (one of the postulated mechanisms of glaucomatous damage),6 and as an agent that may offer a modicum of neuroprotection by inhibiting the calcium influx that is an inherent part of apoptosis.7 To date, optic nerve head concentrations of topically applied betaxolol necessary to produce these additional benefits have not been demonstrated, and there has been no clear, adequately controlled, and robust clinical evidence to support these speculations. Particularly in Europe, other β blockers, such as carteolol, have been available. Possible advantages for some of these molecules include differences in membrane stabilisation properties and partial agonist activity. In Germany, for example, …

BACKGROUND To assess if the vasorelaxing properties of the ocular hypotensive beta-blocker carteolol could share some pharmacological features of calcium-channel antagonists in isolated porcine ciliary arteries. METHODS In a myograph system (isometric force measurement), quiescent vessels were contracted with increasing concentrations of potassium chloride (KCl: 4.7 - 30 mM) in the presence of different concentrations of extracellular calcium (Ca (++): 0 - 10 mM) and/or carteolol (0 - 1 mM). Vessels precontracted with 20 mM KCl were exposed (cumulative manner) to carteolol (0.03 - 3 mM) in the presence of different concentrations of Ca (++) (0.25, 2.5, 10 mM). Contractions and relaxations are expressed in percent of 100 mM and 20 mM KCl-induced contractions, respectively (mean +/- SEM). RESULTS Contractions induced by 30 mM KCl (99.0 +/- 4.8 %) were abolished in the absence of Ca (++) and markedly inhibited in the presence of carteolol (1 mM: 40.6 +/- 4.0 %). The inhibitory effect of carteolol on KCl-induced contractions was potentiated (0.25 mM: 6 +/- 2 %) by decreasing and reversed (10 mM: 94 +/- 5 %) by increasing Ca (++) concentrations. Vessels precontracted with KCl were relaxed by carteolol (maximum: 82 +/- 9 %), an effect potentiated (102 +/- 10 %) by lowering or inhibited (27 +/- 11 %) by increasing Ca (++) concentrations. DISCUSSION The present in vitro pharmacological study, for which in principle no clinical interpretation should be made, suggests that carteolol shares, at rather high concentrations, some characteristics that apparently could mimic certain effects of calcium-channel blockers.

Glaucoma and ocular hypertension are highly prevalent conditions in individuals over the age of 40 and are commonly seen together in patients with cardiovascular disease. Many of the antiglaucoma medications, when systemically absorbed, affect the sympathetic and parasympathetic nervous systems of patients and can cause cardiovascular toxicity. Such adverse effects are frequently associated with the long-term use of potentially toxic agents in elderly people, who are most prone to chronic eye disease. Moreover, patients may not associate their symptoms with the topical eye medications, and consequently may not report adverse drug effects. Drug-drug interactions can also occur when patients are taking medications for both cardiovascular disease and glaucoma. This review focuses on beta-adrenergic blockers as topical antiglaucoma medications and other topical antiglaucoma drugs. The systemic toxicity of these agents is reviewed, along with the possible drug interactions. Brief mention is also made of other antiglaucoma medications used alone and in combination with topical beta-blockers.

We have shown that chronic treatment with carteolol, a non-selective beta-adrenergic receptor antagonist, improved left ventricular (LV) function and survival in an avian model of dilated cardiomyopathy (DCM). The aim of the present study was to compare ex vivo heart function with and without beta-agonist and antagonist challenge. We investigated whether intracoronary infusion of a beta-blocker, carteolol or beta-agonist, isoproterenol decreased contractility. In the DCM group, isoproterenol resulted in a significantly greater increase in heart rate (71% vs. 28% compared to control hearts). To investigate the mechanism for the increase in heart rate, we exposed spontaneously beating neonatal cardiomyocytes to serum immunoglobulin (IgG) isolated from DCM animals. Serum IgG resulted in a significant increase in spontaneous beating rate in neonatal rat cardiomyocytes that was blocked by pre-treatment with a beta-blocker. Carteolol challenge did not significantly change heart rate but did significantly increase LV peak pressure in DCM hearts (62%) while coronary artery flow remained unchanged (2.7+/-0.1 vs 2.7+/-0.5 ml/min/g). These results show that 1) beta-receptor stimulation results in a greater tachycardic response in DCM animals, and 2) carteolol challenge improves myocardial contractility in hearts from DCM animals independent of heart rate or changes in coronary artery flow.

Carteolol is a nonselective adrenergic blocking agent. The aim of this study was to evaluate the effect of topical carteolol on retrobulbar hemodynamics in patients with normal tension glaucoma (NTG).Twelve NTG patients received twelve-week topical treatment of 2% carteolol. Color Doppler imaging (CDI) was used to evaluate the hemodynamic effects before and after drug therapy. Measurements were obtained from the central retinal artery (CRA), the lateral posterior ciliary artery (LPCA) and the medial posterior ciliary artery (MPCA). From each vessel, peak systolic velocity (PSV), end-diastolic velocity (EDV), resistance index (RI) and Gosling's pulsatility index (PI) were collected and analyzed.After topical carteolol treatment for twelve weeks, mean resistance index reduced significantly from 0.83 to 0.74 in the CRA (p = 0.03), from 0.74 to 0.68 in the LPCA (p = 0.09). Moreover, mean pulsatility index of the LPCA decreased from 1.45 to 1.26 (p = 0.08).Twelve weeks of 2% carteoiol treatment may decrease the vascular resistance in NTG patients possibly due to the intrinsic sympathomimetic activity (ISA) of carteolol.

Quaternary ammonium ions have been demonstrated to induce apoptosis correlated with superoxide anion production in vitro. The purpose of this study was to further investigate the mechanisms of benzalkonium chloride (BAC), unpreserved and preserved beta-blocker eye-drops-induced programmed cell death, with special attention to the roles of mitochondrial transmembrane potential and intracellular reduced glutathione.Chang conjunctival cells were incubated with different concentrations of unpreserved or preserved timolol (0.1%, 0.25%, and 0.4%), or carteolol (1% and 2%), or BAC (0.0001% to 0.01%) for 15 minutes, or for 15 minutes with a 24-hour recovery period in normal medium. Cellular viability (neutral red test), mitochondrial activity (rhodamine 123 test), intracellular reduced glutathione (monochlorobimane test), DNA condensation (Hoechst 33342 test), and reactive oxygen species (ROS) production (dichlorofluorescein diacetate and hydroethidine tests) were evaluated using microplate cold-light cytofluorometry.A significant, concentration-dependent decrease in cellular viability was found with preserved beta-blockers and with BAC alone, whereas unpreserved preparations did not show any toxicity. Only preserved beta-blockers induced chromatin condensation associated with an alteration of mitochondrial activity and a decrease of glutathione, suggesting an apoptotic phenomenon. BAC increased glutathione after 15 minutes, whereas a decrease was observed after a recovery period. ROS production was found with preserved formulations at significantly higher levels than those observed with unpreserved drugs.This in vitro study demonstrates that oxidative stress, evidenced by enhanced ROS production and mitochondrial injury rather than by cellular glutathione depletion, is a mechanism involved in apoptosis induced by preservative-containing eye-drops.

AIM To determine the long term efficacy of monotherapy with topically applied β blocking agents and to determine whether selective β blockers were able to preserve the visual field more effectively than non-selective agents. METHOD A prospective randomised, open, comparative study of three topically applied β blockers—timolol, betaxolol, and carteolol—was carried out on 153 patients (280 eyes) with newly diagnosed open angle glaucoma. Those patients who were not withdrawn were followed by the same observers for a minimum of 2 years and a maximum of 7 years, with clinical observations, Goldmann tonometry and 24.2 Humphrey visual field analysis. RESULTS All three drugs lowered the IOP significantly from untreated levels but betaxolol took up to 12 months in some instances to reach the maximum pressure reduction. After 7 years only 43% of the eyes begun on timolol, 34% of those started on carteolol, and 29% of those on betaxolol were still being treated with these medications alone. Visual fields were analysed throughout the trial by CPSD and MD and at the end by linear regression analysis (progressor). The visual fields remained the same without apparent improvement or deterioration throughout the period of follow up. Eight patients (11 eyes) were withdrawn because of continuing field loss in spite of reduction in IOP (six using carteolol and five using betaxolol). CONCLUSIONS Analysis shows that less than half the eyes initially treated with topical β blockers might be expected to still be being treated with their original medication after 5 years. The rest required either additional medication or trabeculectomy. There was no statistically significant improvement or deterioration in the visual fields over a 7 year period. On the evidence of this trial there are no particular advantages in using selective β blockers.

In this study, we attempted to further characterize atypical beta-adrenoceptors on the guinea pig duodenum. (-)-Enantiomers of isoprenaline and noradrenaline were more potent than its (+)-enantiomers. The isomeric activity ratios ((+)/(-)) were less than those obtained in the guinea pig atria and trachea. The concentration-response curves to catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline), to the selective beta(3)-adrenoceptor agonist, BRL37344 ((R*, R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxyacetic acid sodium), and to the non-conventional partial beta(3)-adrenoceptor agonist, (+/-)-CGP12177A ((+/-)-[4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride), were resistant to blockade by (+/-)-pindobind, the beta-adrenoceptor alkylating agent. (-)-Noradrenaline and (-)-adrenaline were more potent than dopamine and (-)-phenylephrine, respectively. Selective beta(2)-adrenoceptor agonists possess agonistic activities at atypical beta-adrenoceptors. (+/-)-Propranolol and (+/-)-bupranolol had no agonistic effect, whereas (+/-)-alprenolol, (+/-)-pindolol, (+/-)-nadolol, (+/-)-CGP12177A and (+/-)-carteolol exhibited agonistic activities at atypical beta-adrenoceptors. These results suggest that pharmacological properties of atypical beta-adrenoceptors differ from those of conventional beta(1)- and beta(2)-adrenoceptors on the guinea pig.

Alginic acid was evaluated as a potential vehicle in ophthalmic solutions for prolonging the therapeutic effect of carteolol. This anionic vehicle was expected to slow down drug elimination by the lacrimal flow, both by undergoing in-situ gel formation and by interacting with the mucus. In vitro studies indicated that carteolol is released slowly from alginic acid formulations, suggesting an ionic interaction. The adhesive behavior of alginic acid solution was better than that of another polymer, hydroxyethylcellulose (HEC). Intraocular pressure (IOP) measurements of rabbit eyes treated with a 1% carteolol formulation with or without alginic acid showed that this polymer significantly extended the duration of the pressure-reducing effect of carteolol to 8 h. The increased ocular bioavailability of 1% carteolol in the presence of alginic acid led to an equivalent concentration in the target tissue although administration was only once a day compared with twice a day for 1% carteolol alone. The overall results of this study indicate that the alginic-acid vehicle is an excellent drug carrier, well tolerated, and could be used for the development of a long-acting ophthalmic formulation of carteolol.

The partial agonist activities of carteolol were investigated on atypical beta-adrenoceptors of duodenum on the guinea pig. Carteolol produced a concentration-dependent relaxation of the guinea pig duodenum (pD(2)=4.85), which was not significantly affected by propranolol (1 microM). In the presence of propranolol (1 microM), however, the non-selective beta(1)-, beta(2)- and beta(3)-adrenoceptor antagonist, bupranolol (30 microM), caused a rightward shift of the concentration-response curves for carteolol (apparent pA(2)=5.31). Moreover, carteolol (10 microM) weakly, but significantly, antagonized the relaxations in response to catecholamines (isoprenaline, noradrenaline and adrenaline), to a selective beta(3)-adrenoceptor agonist, (R*, R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]pheno xyacetic acid sodium salt (BRL37344), and to a non-conventional partial beta(3)-adrenoceptor agonist, [4-[3-[(1, 1-dimethylethyl)amino]-2-hydroxypropoxy]-1, 3-dihydro-2H-benzimidazol-2-one] hydrochloride (CGP12177A), also in the guinea pig duodenum (apparent pA(2)=5.77, 5.92, 6.05, 6.56 and 5. 58, respectively). These results suggest that the partial agonist effects of carteolol are mediated by atypical beta-adrenoceptors in the guinea pig duodenum.

Betaxolol, a beta(1)-adrenoceptor antagonist used for the treatment of glaucoma, is known to be neuroprotective in paradigms of ischaemia/excitotoxicity. In this study, we examined whether betaxolol and other beta-adrenoceptor antagonists interact directly with neurotoxin binding to sites 1 and 2 of the voltage-sensitive sodium channel (Na(+) channel) in rat cerebrocortical synaptosomes. Betaxolol inhibited specific [(3)H]-batrachotoxinin-A 20-alpha-benzoate ([(3)H]-BTX-B) binding to neurotoxin site 2 in a concentration-dependent manner with an IC(50) value of 9.8 microM. Comparison of all the beta-adrenoceptor antagonists tested revealed a potency order of propranololbetaxolol approximately levobetaxolollevobunolol approximately carteolol/=timololatenolol. None of the drugs caused a significant inhibition of [(3)H]-saxitoxin binding to neurotoxin receptor site 1, even at concentrations as high as 250 microM. Saturation experiments showed that betaxolol increased the K(D) of [(3)H]-BTX-B binding but had no effect on the B(max). The association kinetics of [(3)H]-BTX-B were unaffected by betaxolol, but the drug significantly accelerated the dissociation rate of the radioligand. These findings argue for a competitive, indirect, allosteric mode of inhibition of [(3)H]-BTX-B binding by betaxolol. Betaxolol inhibited veratridine-stimulated Na(+) influx in rat cortical synaptosomes with an IC(50) value of 28. 3 microM. Carteolol, levobunolol, timolol and atenolol were significantly less effective than betaxolol at reducing veratridine-evoked Na(+) influx. The ability of betaxolol to interact with neurotoxin site 2 of the Na(+) channel and inhibit Na(+) influx may have a role in its neuroprotective action in paradigms of excitotoxicity/ischaemia and in its therapeutic effect in glaucoma.

Purpose To compare the effects of 0.5% timolol maleate, 2% carteolol, and 0.3% metipranolol on intraocular pressure (IOP) in 45 patients with primary open-angle glaucoma (POAG) and ocular hypertension. A secondary goal of this study was to evaluate the ocular and systemic side effects of these medications. Methods Measurements of IOP were taken at baseline (pretreatment) and 2, 6, and 12 hours after instillation on treatment days 15, 30, 60, and 90. Mean sensitivity (MS) and mean defect (MD) values of perimetry before and after treatment and the effects of the three beta blockers on serum lipid profiles were determined. Ocular and systemic side effects were recorded. Results The most prominent IOP lowering effect was noted with metipranolol at 2 and 6 hours on day 15, and with timolol maleate at 12 hours on day 15 and at all hours of the subsequent days on which measurements were taken. Timolol maleate produced a significant decrease in IOP at 12 hours on day 15 compared with carteolol. There was not a statistically significant difference between the MS and MD values on perimetry before and after treatment for any treatment. There was a statistically significant decrease in levels of total cholesterol and high-density lipoprotein (HDL) cholesterol and a significant increase in triglyceride levels; these changes were observed for all treatments. Conclusion The effects of the three medications were not statistically different from each other in terms of IOP reduction and visual field changes. Careful monitoring of blood lipid levels is necessary with long-term treatment with beta blockers, because these agents reduced serum levels of HDL and total cholesterol while increasing triglycerides. Such changes in lipid levels could lead to increased incidence of complications, particularly in patients with atherosclerosis or coronary heart disease.

AIM To evaluate the effects of β blockers used in ophthalmology on the release of histamine from mixed cell preparations containing human leucocytes and basophils. METHODS A mixed leucocyte and basophil preparation was obtained from venous blood of healthy non-atopic volunteers. Cell preparations were then incubated with betaxolol, metipranolol, timolol, or carteolol. After incubation for 1 hour the histamine content of the supernatant was analysed by automated fluorometric analysis. Cell viability was tested by measuring lactate dehydrogenase (LDH) concentrations. RESULTS Betaxolol and metipranolol in concentrations between 10 –2 M and 10 –3 M liberated histamine from human blood cells in a dose dependent manner. Carteolol and timolol had no effect on histamine at these concentrations. At the same concentrations LDH was also detected in the supernatants of cell suspensions incubated with metipranolol or betaxolol. CONCLUSIONS Betaxolol and metipranolol induce substantial histamine release from human leucocytes, probably as a result of their cytotoxic effect.

Effects of the R(+)- and S(−)-isomers of befunolol and carteolol, β-adrenoceptors with intrinsic sympathomimetic activity, on the rabbit intraocular pressure were tested. The intraocular pressure was decreased by instillation of the R(+)- and S(−)-isomers of befunolol (0.1 and 0.3%) and of carteolol (1.0%) to the eye and attained the minimum level at 60 min. However, 0.3% of the R(+)- and S(−)-isomers of carteolol did not influence the pressure. The corresponding time courses for the intraocular pressure for the R(+)- and S(−)-isomers did not differ, suggesting that in the treatment of glaucoma, the therapeutic advantage of the R(+)-isomers of befunolol and carteolol may be similar to the S(−)-isomers.Key words: intraocular pressure, β-adrenoceptor blockade, R(+)-isomer, stereoselectivity.

A beta-adrenoceptor blocker and an anticholinergic agent are often prescribed concomitantly for the treatment of neuroleptic-induced akathisia. The aim of this study was to investigate possible pharmacokinetic interactions of neuroleptic haloperidol with the beta-blocker carteolol and the anticholinergic biperiden. In a 5-step, open-labeled, oral single-dose study, eight healthy male volunteers received 2 mg haloperidol, 10 mg carteolol hydrochloride, and 2 mg biperiden hydrochloride: first each drug alone, then a combination of haloperidol and carteolol, and then all three drugs concurrently. Serum concentrations of haloperidol, carteolol, and biperiden were determined up to 24 hr postdosing, and a safety evaluation was conducted throughout the study. Carteolol increased the area under the haloperidol serum concentration-time curve (AUC0-t) 1.4-fold (P = 0.0014) and decreased the serum clearance of haloperidol up to 67% (P = 0.0127). Biperiden reduced the serum haloperidol concentrations increased by the administration of carteolol. No significant changes of the serum pharmacokinetics of carteolol and biperiden were found as a result of any drug combinations. Adverse events of the central nervous system such as sleepiness and changes in pupil size were observed, but all were mild with clinical insignificance.

The effect of betaxolol on the specific binding of [ 3 H ]diltiazem and [ 3 H ]nitrendipine to rat cortical membranes was examined. Betaxolol inhibited specific [ 3 H ]diltiazem and [ 3 H ]nitrendipine binding with IC 50 values of 19.7 and 46.3 μM, respectively. The effect of betaxolol on L-type Ca 2+ channels showed little stereospecificity, since similar inhibitions of radioligand binding were observed with both racemic betaxolol and l -betaxolol. The dissociation kinetics of [ 3 H ]diltiazem were unaffected by 30 μM betaxolol, whereas it increased the [ 3 H ]nitrendipine dissociation rate, thus suggesting that betaxolol directly interacts with the benzothiazepine binding site and allosterically modulates the dihydropyridine binding site. Carteolol, propranolol and timolol were also found to inhibit both specific [ 3 H ]diltiazem and [ 3 H ]nitrendipine binding to rat cortical membranes, but with less potency than betaxolol. The ability of betaxolol to interact with L-type Ca 2+ channels may have a role in its therapeutic effects in the management of systemic hypertension and in reducing neuronal death as occurring in glaucoma.

· Background: We set out to clarify the mechanisms involved in the effectiveness of β-adrenergic receptor antagonists on the ocular circulation. · Methods: The effects of three β antagonists, timolol, betaxolol and carteolol, on the isolated rabbit ciliary artery were investigated in vitro using isometric tension recording methods. · Results: Phenylephrine dose-dependently contracted ciliary artery smooth muscle, and bunazosin (1 µM) shifted this dose-response curve to the right. Isoproterenol, on the other hand, had no effect up to the concentration of 1 mM. Betaxolol and timolol had no effect on the ciliary artery. However, carteolol dose-dependently contracted this muscle from a concentration of 1 µM. After precontraction by excess-[K]0 solutions, application of betaxolol or timolol dose-dependently provoked relaxation; the minimum concentration of betaxolol or timolol required to generate the relaxation was 100 µM and 300 µM, respectively. Carteolol did not generate relaxation at concentrations up to 1 mM. After pretreatment with L-NAME (300 µM), the amplitude of relaxation induced by 10 µM carbachol was reduced to 33.0±20.2%, while betaxolol- or timolol-induced relaxation was unchanged. Diltiazem (10 µM) induced relaxation which was not inhibited by pretreatment with L-NAME. · Conclusion: Betaxolol and timolol could directly relax rabbit ciliary artery in vitro at relatively high concentrations, and relaxation was not due to NO released from the preparation. Presumably, this relaxation occurs through action similar to Ca antagonists. However, the clinical importance of this effect is not yet clear. Carteolol had no relaxant effect in vitro.

To evaluate the effects of topical carteolol or timolol on tissue circulation in the iris and posterior choroid.After a topical instillation of 20 microl of 2% carteolol, 0.5% timolol, or physiological saline (for control) into one eye, and physiological saline into the other eye of pentobarbital-anesthetized Dutch pigmented rabbits, normalized blur value; a quantitative index of tissue blood velocity in the iris (NB(iris)) and posterior choroid (NB(cho)) was obtained using the laser-speckle method. Intraocular pressure (IOP), blood pressure and pulse rate were serially monitored for 2 hours after instillation. Using separate groups of rabbits, NB(iris) and IOP were measured before and after 20-day twice-daily unilateral treatment of carteolol or timolol.After a single instillation of carteolol, NB(iris) was significantly greater only in the treated eyes than control eyes (P = 0.0050, repeated measures two-way ANOVA), while NB(cho) showed no significant change. IOP in the treated eyes significantly reduced (P = 0.0005). Bilateral reductions of tissue vascular resistance in the iris were found after carteolol instillation (P = 0.0183 approximately 0.0322). After timolol instillation, serial changes in NB(iris) and NB(cho) in the treated eyes were significantly different from those in control eyes (P = 0.0129, 0.0031), while there were no significant differences at any of time points (Mann-Whitney test); IOP in both eyes was significantly reduced (P = 0.0096 approximately 0.0005); tissue vascular resistance in the iris and posterior choroid showed no significant changes. After 20-day treatment, NB(iris) in the both eyes of carteolol-treated rabbits significantly increased from the baseline (P = 0.0280, 0.0425, Wilcoxon signed rank test) and NB(iris) in timolol-treated eyes significantly decreased (P = 0.0280).A single instillation of topical carteolol significantly increased the iris tissue blood velocity in the treated eye and reduced the tissue vascular resistance in both eyes. Topical timolol tended to decrease tissue blood velocity in the iris and choroid of the treated eye, but showed no significant effects on tissue vascular resistance in the both tissues.

Broad-breasted white turkey poults fed furazolidone developed dilated cardiomyopathy (DCM) characterized by ventricular dilatation, decreased ejection fraction, β1-receptor density, sarcoplasmic reticulum (SR) Ca2+-ATPase, myofibrillar ATPase activity, and reduced metabolism markers. We investigated the effects of carteolol, a β-adrenergic blocking agent, by administrating two different dosages (0.01 and 10.0 mg/kg) twice a day for 4 wk to control and DCM turkey poults. At completion of the study there was 59% mortality in the nontreated DCM group, 55% mortality in the group treated with the low dose of carteolol, and 22% mortality in the group treated with the high dose of carteolol. Both treated groups showed a significant decrease in left ventricle size and significant restoration of ejection fraction and left ventricular peak systolic pressure. Carteolol treatment increased β-adrenergic receptor density, and the high carteolol dose restored SR Ca2+-ATPase and myofibrillar ATPase activities, along with creatine kinase, lactate dehydrogenase, aspartate transaminase, and ATP synthase activities, to normal. These results show that β-blockade with carteolol improves survival, reverses contractile abnormalities, and induces cellular remodeling in this model of heart failure.

PURPOSE: To determine the effect on serum lipid levels of carteolol hydrochloride 1.0% or timolol maleate 0.5% given twice a day to women age 60 years and older with primary open-angle glaucoma or ocular hypertension. METHOD: We included 112 patients in this double-masked, randomized, multicenter trial. Fasting clinical laboratory studies were evaluated at baseline and at 12 weeks. Patients were instructed not to change their dietary, alcohol consumption, or exercise habits during the study. RESULTS: For the carteolol group, the high-density lipoprotein (HDL) and total cholesterol/high-density lipoprotein (TC/HDL) ratio at baseline of 50.1 ± 1.5 mg/dl and 4.7 ± 0.2 changed by the 12-week visit to 51.3 ± 1.9 mg/dl ( P = .25) and 4.6 ± .02 ( P = .47), respectively. For the timolol maleate group, the baseline HDL and TC/HDL ratio of 53.6 ± 2.2 mg/dl and 4.4 ± 0.2 changed to 50.2 ± 1.9 mg/dl ( P P = .001), respectively, at the 12-week visit. Carteolol patients showed no significant change from baseline, whereas the HDL ( P P = .001) significantly in the timolol maleate group. There also was a significant difference in the change from baseline at 12 weeks between carteolol and timolol maleate groups for the HDL and TC/HDL ratio ( P = .01 and .012, respectively). No differences in TC, low-density lipoprotein (LDL), or triglycerides (TG) or in changes from baseline were observed between groups at 12 weeks ( P > .05). At 12 weeks, no differences were observed between carteolol and timolol maleate groups in intraocular pressure or safety ( P > .05), except that patients given carteolol demonstrated fewer solicited ocular symptoms ( P = .007). CONCLUSIONS: Carteolol appears to be neutral in its effect on serum lipid levels, whereas timolol maleate adversely affects the HDL and TC/HDL ratio in women age 60 years and older with ocular hypertension or primary open-angle glaucoma.