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The purpose of this study was to determine whether carteolol eye drops, a β-adrenoceptor antagonist used as an intraocular hypotensive agent, has protective effects against the light-induced oxidative stress in retina. Dark-adapted pigmented rats were pre-treated with topical carteolol ophthalmic solution or saline and then exposed to visible light. The effects on electroretinogram (ERG), morphology, oxidative stress, and expression of mRNAs in the retinas were determined. The l-buthionine-(S,R)-sulfoximine (BSO)/glutamate-induced oxidative stress in 661 W cells, a murine photoreceptor cell line, was evaluated by cell death assays, production of reactive oxygen species (ROS), and activation of caspase. In vivo studies showed that exposure to light caused a decrease in the amplitudes of ERGs and the outer nuclear layer (ONL) thickness and an increase of the 8-hydroxy-2′-deoxyguanosine (8-OHdG)-positive cells in the ONL. These changes were significantly reduced by pre-treatment with carteolol. Carteolol also significantly up-regulated the mRNA levels of thioredoxin 1 and glutathione peroxidase 1 compared to saline-treated group. Moreover, carteolol and timolol, another β-adrenoceptor antagonist, significantly inhibited BSO/glutamate-induced cell death and reduced caspase-3/7 activity and ROS production in vitro. Therefore, carteolol could protect retina from light-induced damage with multiple effects such as enhancing the antioxidative potential and decreasing the intracellular ROS production. Keywords: Carteolol hydrochloride, Light-induced retinal damage, Oxidative stress, Antioxidative potential, Reactive oxygen species

Carteolol is a frequently used nonselective β-adrenoceptor antagonist for glaucoma and ocular hypertension treatment, and its repeated/prolonged usage might be cytotoxic to the cornea, especially the outmost human corneal epithelium (HCEP). The aim of the present study was to characterize the cytotoxicity of carteolol to HCEP and its underlying cellular and molecular mechanisms using an in vitro model of HCEP cells. After HCEP cells were treated with carteolol at concentrations varying from 2% to 0.015625%, the cytotoxicity, apoptosis-inducing effect and pro-apoptotic pathway was investigated, respectively. Our results showed that carteolol at concentrations above 0.03125% induced time- and dose-dependent growth retardation, cytopathic morphological changes and viability decline of HCEP cells. Moreover, carteolol induced G1 phase arrest, plasma membrane permeability elevation, phosphatidylserine externalization, DNA fragmentation, and apoptotic body formation of HCEP cells. Furthermore, carteolol also induced activation of caspase-9 and -3, disruption of mitochondrial transmembrane potential, up-regulation the cytoplasmic amount of cytochrome c and apoptosis-inducing factor, and up-regulation of pro-apoptotic Bax and Bad, down-regulation of anti-apoptotic Bcl-2 and Bcl-xL. In conclusion, carteolol above 1/64 of its clinical therapeutic dosage has a time- and dose-dependent cytotoxicity to HCEP cells, which is achieved by inducing apoptosis via triggering Bcl-2 family protein-mediated mitochondrial pro-apoptotic pathway.

A rapid, sensitive and selective method for the simultaneous quantification of carteolol and dorzolamide in rabbit aqueous humor (AH) and ciliary body (CB) has been developed and validated using reversed phase-high performance liquid chromatography (RP-HPLC) with isocratic elution coupled with atmospheric pressure chemical ionization mass spectrometry/mass spectrometry (APCI-MS/MS). The analytes and nadolol (used as internal standard, IS) were purified from AH by protein precipitation. The sample preparation from CB was based on a two steps extraction procedure at different pH, utilizing a liquid–liquid extraction with a mixture of ethyl acetate, toluene and isopropanol 50:40:10 (v/v) at pH 8, followed by a second extraction with ethyl acetate at pH 11. The combined organic extracts were then back extracted into 0.1% aqueous trifluoroacetic acid (TFA). The accuracy and precision values, calculated from three different sets of quality control samples analyzed in sestuplicate on three different days, were within the generally accepted criteria for analytical methods (

This study evaluates ocular (iris, ciliary body and ciliary process) and nonocular (atria and lung) beta-adrenoceptors in rabbit to characterize the plasma membrane beta-adrenoceptors and binding affinities of beta-adrenoceptor antagonists.The tissue segment binding method with a hydrophilic radioligand (-)-4-[3-t-butylamino-2-hydroxypropoxy]-[5,7-(3)H]benzimidazol-2-one ([(3)H]-CGP12177) was employed.Specific and saturable binding of [(3)H]-CGP12177 to intact tissue segments was detected by using (+/-)-propranolol to define nonspecific binding, showing a single population of plasma membrane binding sites with high affinity. Competition experiments with selective beta(1)- and beta(2)-adrenoceptor antagonists revealed a single population of beta(2)-adrenoceptors in ocular tissues and of beta(1)-adrenoceptors in atria, but mixed populations of beta(1)- and beta(2)-adrenoceptors in 70% and 30%, respectively, in lung. A competition curve for timolol was biphasic in lung and its binding affinity for beta(2)-adrenoceptors was approximately 158-fold higher than for beta(1)-adrenoceptors, indicating the beta(2)-selectivity of timolol. In contrast, competition curves for stereoisomers of befunolol, carteolol, and propranolol were monophasic in all tissues. The (-)-enantiomers of these antagonists were more potent than corresponding (+)-enantiomers in displacing from [(3)H]-CGP12177 binding, and the isomeric potency ratios of befunolol and carteolol were less than those of propranolol.This study with tissue segment binding method suggests that the binding affinity of (-)-enantiomers of beta-adrenoceptor antagonists for plasma membrane beta-adrenoceptors (beta(1)-adrenoceptors of atria, beta(2)-adrenoceptors of ocular tissues, and mixed beta(1)-/beta(2)-adrenoceptors of lung) is higher than that of corresponding (+)-enantiomers and their stereoselectivity is different between beta-adrenoceptor antagonists.

Hypoxia-induced retinal ganglion cell (RGC) death has been implicated in glaucomatous optic neuropathy. However, the precise mechanism of death signaling and how neuroprotective agents affect it are still unclear. The aim of this study is to characterize the mechanisms of hypoxia-induced apoptosis of cultured purified RGCs and to study the neuroprotective effects of beta-adrenergic antagonists. Rat RGCs were purified utilizing a modified two-step immuno-panning procedure. First, the extent of apoptosis in RGCs under hypoxia was quantified. Next, the effects of glutamate-channel antagonists (MK801 or DNQX), Bax inhibiting peptide (BIP), and beta-adrenergic antagonists (betaxolol, nipradilol, timolol or carteolol) on hypoxia-induced RGC death were investigated by the cell viability assay. Third, the effects of beta-adrenergic antagonists on hypoxia-induced increase of intracellular calcium concentrations ([Ca(2+)](i)) and the additional effect of NO scavenger to nipradilol were evaluated. Apoptotic RGC percentages under hypoxia were significantly increased compared to the control. The viability of RGCs under hypoxia was not affected by MK801 or DNQX, whereas it was increased in a dose-dependent manner with exposure to BIP, and to betaxolol, nipradilol, timolol, but not to carteolol. These effective beta-adrenergic antagonists showed no significant change in hypoxia-induced [Ca(2+)](i) levels. The NO scavenger alleviated neuroprotective effect by nipradilol. In conclusion, purified RGC damage induced by hypoxia involves Bax-dependent apoptotic pathway, but mostly independent of glutamate receptor-mediated excitotoxicity. Betaxolol, timolol and nipradilol showed a protective effect against hypoxia-induced RGC death, which was thought to be irrelevant either to calcium channel or beta-adrenoceptor blocking effects.

Purpose: To evaluate the comparative efficacy of latanoprost monotherapy versus combined carteolol and pilocarpine therapy in patients with newly diagnosed glaucoma. Methods: Masked randomized prospective trial. This study included 51 patients (64 eyes) with newly diagnosed glaucoma or ocular hypertension. The cases were randomly divided into two treatment groups for administration of latanoprost 0.005% once daily, or of carteolol 2% twice daily and pilocarpine 2% twice daily. Mean diurnal intraocular pressure (IOP) was measured at baseline, week 2, week 4, and month 3 after the beginning of treatment. Changes in mean IOP from baseline to the 3-month visit were determined by an analysis of variance. Results: Mean diurnal IOP values were 25.1 ± 3.1 mm Hg and 25.5 ± 2.5 mm Hg at baseline in the latanoprost monotherapy group and in the carteolol-plus-pilocarpine group, respectively. Diurnal IOP was significantly decreased from baseline to 3 months in both groups (P < .001). At this time point, latanoprost monotherapy had reduced mean diurnal IOP by 7.2 ± 2.5 mm Hg (28.7%) and carteolol plus pilocarpine had reduced mean diurnal IOP by 7.4 ± 2.7 mm Hg (29%). There was no difference between the groups in terms of their IOP reduction effect (P = .51). Decreased visual acuity and twilight vision, blurred vision, and headache were more frequent in the carteolol-plus-pilocarpine group than in the latanoprost group (P < .05). Conclusions: We concluded that latanoprost monotherapy was at least as effective as the carteolol-pilocarpine combination therapy in reducing mean diurnal IOP in newly diagnosed glaucoma or ocular hypertension.

The properties of the beta1-/beta2-adrenoceptor partial agonist carteolol were investigated in atypical beta-adrenoceptors on the guinea pig gastric fundus. Carteolol induced concentration-dependent relaxation in this tissue (pD2 = 5.55, intrinsic activity = 0.94). However, a combination of the selective beta1-adrenoceptor antagonist atenolol (100 microM) and the selective beta2-adrenoceptor antagonist butoxamine (100 microM) produced only small rightward shifts in the concentration-response curves of carteolol in the gastric fundus (pD2 = 4.91, intrinsic activity = 0.94). In the presence of both atenolol (100 microM) and butoxamine (100 microM), the non-selective beta1-, beta2- and beta3-adrenoceptor antagonist (+/-)-bupranolol (10-100 microM) caused a concentration-dependent right-ward shift of the concentration-response curves for carteolol in the guinea pig gastric fundus. Schild plot analyses of the effects of (+/-)-bupranolol against carteolol gave the pA2 value of 5.29 and the Schild slope was not significantly different from unity. Furthermore, carteolol (10 microM) weakly but significantly antagonized the relaxant responses to catecholamines ((-)-isoprenaline, (-)-noradrenaline and (-)-adrenaline), a selective beta3-adrenoceptor agonist BRL37344 ((R*,R*)-(+/-)-4-[2-[(2-(3-chlorophenyl)-2-hydroxyethyl)amino]propyl]phenoxy-acetic acid sodium salt) and a non-conventional partial beta3-adrenoceptor agonist (+/-)-CGP12177A ([4-[3-[(1,1dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazol-2-one] hydrochloride) in the guinea pig gastric fundus. These results suggest that the partial agonistic effects of carteolol are mediated by atypical beta-adrenoceptors in the guinea pig gastric fundus.

Purpose: To investigate the effect of an intravenous infusion of carteolol on tissue blood flow in the optic nerve head (ONH) of rabbits. Methods: Rabbits received either a 3-week topical instillation, or a single intravenous injection (10, 20, 30 μg/kg) or a continuous intravenous injection (2.5, 5, 20, 40, 80 μg/kg per hour) of carteolol. The plasma carteolol level was determined by the gas chromatography negative-ion chemical ionization mass spectrometric method. The ONH blood flow was determined by the hydrogen clearance method. Results: The plasma level of carteolol after a 3-week instillation was 5.55 ng/mL, and a continuous intravenous injection (5 μg/kg per hour) led to approximately the same plasma level. The continuous intravenous infusion of 5 μg/kg per hour of carteolol significantly increased the ONH blood flow compared to the controls from 30 minutes to 2 hours after the beginning of the infusion (n = 10). The mean blood pressure and intraocular pressure (n = 6) were not significantly changed during the continuous intravenous infusion of carteolol. Conclusions: These results suggest that the plasma carteolol level in rabbits after long-term instillation can increase the ONH blood flow. We conclude that the increase resulted from a reduction in the vascular resistance in the ONH.

Purpose To evaluate the ocular hypotensive effect and safety of carteolol hydrochloride 1% vs timolol maleate 0.5%. Methods One hundred seventy-six patients with ocular hypertension or primary open-angle glaucoma were randomly assigned to receive either carteolol 1% twice a day or timolol maleate 0.5% solution twice a day in a randomized, double-masked, multicenter, parallel-group, active-control comparison trial during a 3-month period. Results After 12 weeks, carteolol 1% reduced the mean ± SE intraocular pressure from 25.0 ± 0.3 to 19.5 ± 0.3 mm Hg; timolol maleate 0.5% reduced the mean intraocular pressure from 25.2 ± 0.3 to 19.6 ± 0.3 mm Hg. The mean difference in trough intraocular pressure between carteolol and timolol maleate of –0.14 mm Hg was not significantly ( P = .745) different (95% confidence limits, –0.97 to 0.70 mm Hg). Trough pulse and blood pressure also showed no consistent statistically significant differences between groups. The 2-hour postdose pulse, however, demonstrated a greater decrease in the timolol maleate than in the carteolol group ( P P = .039), and the carteolol group reported fewer ocular symptoms than the timolol maleate group did ( P Conclusions Both carteolol 1% and timolol maleate 0.5% are highly effective in lowering intraocular pressure when measured at the end of the dosing interval. Carteolol 1% demonstrates an ocular hypotensive effect and safety profile similar to those of timolol maleate 0.5% solution.

Purpose To compare the effects of topical timolol maleate 0.5% and carteolol hydrochloride 1% on pulse rate and blood pressure. Methods In a randomized, double-masked, parallel-design, multicenter clinical trial, we compared the effects of timolol and carteolol on pulse rate and blood pressure measured by 24-hour ambulatory blood pressure monitoring in 169 adult patients with either ocular hypertension or primary open-angle glaucoma. Results From noon to 8 PM, baseline mean pulse rate of 82 to 83 beats per minute (bpm) had decreased by 4 to 6 bpm in both groups after 4 weeks of therapy with timolol or carteolol. From midnight to 4 AM, the pulse rate in the carteolol group was significantly above baseline (P = .005), while the timolol group was significantly below baseline (P Conclusions Timolol causes significantly lower mean heart rate during the nighttime and more nocturnal bradycardia than carteolol does in patients with ocular hypertension and primary open-angle glaucoma. These differences may be because of the intrinsic sympathomimetic activity of carteolol.

Carteolol (CRT) is currently under development as a potential therapeutic agent for the treatment of open angle glaucoma. The purpose of the present work is to develop and validate a stability indicating assay method and its application to estimate CRT in aqueous humour and study the pharmacokinetic parameters. An ultra performance liquid chromatographic tandem mass spectroscopy (UPLC–MS/MS) method was developed and validated for the quantitative determination of CRT in rabbit aqueous humour, using propranolol as the internal standard (I.S.). Aqueous humour samples were prepared by a simple liquid–liquid extraction technique (LLE). The analyte and internal standard were separated by an Acquity UPLC BEH C18 (100.0 × 2.1 mm; 1.7 μm) column with a mobile phase of acetonitrile – 2 mM (milli mole) ammonium acetate (90/10, v/v) over 3 min of retention time. Detection was based on the multiple reactions monitoring with the precursor-to-product ion transitions m/z 293.2 → 237.12 for CRT and m/z 260.09 → 183.04 for I.S. The method was validated according to FDA guidelines on the bio-analytical method validation. The method developed was linear (r2 = 0.999) over the concentration range of 1–1000 ng/mL. The selectivity, sensitivity, linearity, accuracy, precision, extraction recovery, and stability were within the acceptable ranges. Forced degradation studies were performed on bulk sample of CRT as per ICH prescribed stress conditions, such as acid, base, oxidative and photolytic to show the forced of the method. Significant degradation was observed during basic stress condition. The pharmacokinetic study of CRT solution and nanoparticles in aqueous humour of rabbit eye was performed and results showed that CRT nanoparticles enhance the ocular bioavailability by 5.61-fold as compared to CRT-solution.

Inert matrix tablets of carteolol hydrochloride were prepared using 50% of Eudragit® RS as a supporting material and a series of fillers: Emcompress®, mannitol, polyethylene glycol 6000 and lactose. Two liquids were used to wet the drug-excipient mixtures: Eudragit® L 12.5% and isopropanol-acetone 6:4 mixture. The affinity of carteolol hydrochloride to the matrix forming material Eudragit® RS (expressed as a Kaff value) was calculated: the higher the pH value, the greater was the value of the Kaff obtained. Each component of the formulations as well as its presence in the matrix systems was identified by differential scanning calorimetry (DSC). The thermal analysis suggested that no drug-excipient interaction occurs during the preparation process. Finally, the dissolution profiles were studied applying three different kinetic models (zero-order, first-order and Higuchi equation). Controlled release profiles were obtained in all the inert matrix compressed tablets studied with the unique exception of lactose used as a filler. The mechanism of release from the matrices was shown to be diffusion-controlled. The dissolution behavior was found to display a biphasic profile in the case of the lots prepared with Eudragit® L 12.5% as wetting liquid of the formulations. Higuchi release rate constants were also calculated.

To assess the effect of carteolol, a beta-blocker, on ischemia and reperfusion, changes in the ultrastructure of myocytes and energy metabolism were studied by 31P-NMR in 41 pig hearts without collateral circulation. The left anterior descending coronary artery was occluded for 20 min and reperfused for 120 min in three groups: seven pigs (group 1, no treatment with carteolol; group 2, pre-ischemia treatment with carteolol (10 micrograms/kg); group 3, post-ischemia treatment with carteolol before reperfusion). Other groups of five pigs were killed after 120 min of ischemia (group 4, no treatment; group 5, pre-ischemia treatment) or 20 min of ischemia (group 6, no treatment; group 7, pre-ischemia treatment). After 20 min of ischemia, ATP was higher in groups 2 (76 +/- 9% of the baseline value) than in group 1 (59 +/- 5%) and group 3 (60 +/- 10%). However, the difference disappeared after 30 min of ischemia. After 120 min of reperfusion, ATP showed much better recovery in group 2 (92 +/- 9%) than in groups 1 (66 +/- 7%) and 3 (68 +/- 10%). Ischemic injury, as viewed by light and electron microscopy, was milder in group 7 than in group 6 after 20 min occlusion, but the myocytes were almost normal after 120 min reperfusion in groups 1 to 3. The heart rate, blood pressure and rate pressure product showed no significant difference among the groups. These results indicate that pre-ischemia treatment with carteolol provided protection against ischemic cellular injury and accelerated the repletion of ATP during reperfusion, but the post-ischemia treatment did not lead to recovery of ATP. Therefore, the favorable effect during reperfusion of pre-ischemia treatment with carteolol depends on its protective effect during ischemia.

Using an in vitro method the authors have investigated whether 8-hydroxycarteolol·HCl (8-OH carteolol) and 8-OH carteolol with benzalkonium chloride affected intact isolated porcine corneas to the same or to a different degree as carteolol·HCl (carteolol) or carteolol with benzalkonium chloride. These ophthalmically used drugs were applied as solutions of varying concentrations to the epithelial surface only, to the endothelial surface only, or to both surfaces of porcine corneas. The resultant opacities were determined using an opacitometer. In general, 8-OH carteolol and 8-OH carteolol with benzalkonium chloride caused less opacity to develop than carteolol and carteolol with benzalkonium chloride. This suggests that 8-OH carteolol may be a safer drug than carteolol for ophthalmic use. It is very interesting to note that compounds with two nitrogens, e.g., 8-OH carteolol, caused greater opacity in the intact cornea when applied to the endothelial surface than when applied to both the epithelial and endothelial surfaces; however, compounds with none or one nitrogen caused greater opacity in the intact cornea when applied to both surfaces than when applied to the endothelial surface.

Purpose: The effect of topical 2% carteolol hydrochloride on the ocular blood flow dynamics in normal human eyes was studied. Materials and Methods: Ten healthy volunteers were studied using color Doppler imaging and scanning laser Doppler flowmetry. In the first experiments, one eye received 30 μl of 2% carteolol hydrochloride twice daily for 7 days and the fellow eye a placebo in a randomized masked manner. The blood flow velocity of the central retinal artery, the ophthalmic artery, and the short posterior ciliary artery, the blood flow volume of the peripapillary retina (PPR), intraocular pressure (IOP), ocular perfusion pressure (OPP) and pulse rate (PR) were measured before treatment, 2 hours after the initial instillation, and after the last instillation on the 7th day. In the control experiments, 30 μl of placebo was instilled in both eyes, and the above parameters were measured according to the same time schedule as in the first experiments. Results: In the carteolol-treated eyes, the systolic maximum (p = 0.012) and diastolic minimum (p = 0.019) blood flow velocities of the ophthalmic artery, and the blood flow volume of the superior (p = 0.003), central (p = 0.001) and inferior (p = 0.000) PPR showed significant increases in the first experiments compared with the control experiments. IOP and OPP in both eyes showed significant reduction in the first experiments compared with the control study. Conclusion: These results indicated that topical carteolol hydrochroride increases the blood flow of the intraorbital microcirculation and PPR.

Interactions of beta-adrenergic partial agonists with the beta-adre- noceptor were studied in isolated guinea-pig taenia caecum. The competitive inhibition curve for specific binding of a high concentration (50 nM) of [3H]-befunolol by befunolol showed a biphasic shape, although the curve for specific binding of a low concentration (1 nM) was monophasic. All the competitive inhibition curves for specific binding of [3H]-befunolol (1 nM and 50 nM) by iso- prenaline and propranolol showed monophasic shapes. These results suggest that befunolol may be able to discriminate two different binding sites of the beta- adrenoceptor: the high affinity site and the low affinity site.

The actions of beta-adrenergic blocking drugs, propranolol, pindolol, timolol, carteolol, sotalol and practolol, were examined regarding effects on crayfish giant axon in an attempt to determine the relationship among chemical structure and local anesthetic activity, and the interaction of these drugs with Ca++. The activities of local anesthetics such as procaine and lidocaine served for comparisons. A conventional microelectrode technique was used to obtain the resting membrane and action potentials. All drugs except sotalol and practolol dose-dependently inhibited the dV/dt and amplitude of the action potential with a slight decrease (less than 6 mV) in the resting membrane potential. The relative potencies of these drugs in the reduction of the dV/dt were as follows: propranolol 13.3, pindolol 1.7, procaine 1.0, lidocaine 0.91, timolol 0.71 and carteolol 0.22. Sotalol and practolol had little activity. The chemical structure of the drugs for local anesthetic action was closely related to that of the lipophilic aromatic group; the most potent activity seen in the naphthyl group. Potentiation of the local anesthetic activity in low Ca++ solution was obtained with pindolol, timolol, carteolol, sotalol and practolol. Reduction of the activity in high Ca++ solution was observed with propranolol, pindolol, timolol, procaine and lidocaine. These results suggest that external Ca++ competes with the local anesthetic action of the beta-adrenergic blocking drugs, at the site of the action potential generating mechanism.

The effects of guanosine and of five guanine nucleotides on sinus rate and contractile force were investigated using the isolated, blood-perfused dog atrium preparation. Guanosine consistently induced a positive chronotropic and inotropic effect which was not suppressed by treatment with a potent beta-adrenoceptor blocking agent, carteolol. GMP, GDP and CTP induced a biphasic chronotropic and inotropic effect. The potencies for inducing the positive effects of GMP, GDP and GTP were almost the same. However, their rank order of potency for inducing negative effects was GTP greater than or equal to GDP greater than GMP. The negative responses to GTP were not inhibited by atropine. Cyclic GMP and dibutyryl cyclic GMP produced only slight negative chronotropic and inotropic effects but not consistently even at larger doses. The positive chronotropic and inotropic responses to norepinephrine were not modified by treatment with dibutyryl cyclic GMP.

Effective treatment of chronic hypertension may be accompanied by a decrease, increase, or no change in the extent of LVH, depending on the pharmacologic properties of the antihypertensive agents employed. Unlike β-adrenoceptor blockers without ISA, β-adrenoceptor blockers with ISA have been reported to increase left ventricular mass despite favorable reductions in blood pressure. To assess further the potential effect of ISA on LVH, we retrospectively evaluated the effect of carteolol, a nonspecific β-adrenoceptor antagonist with strong ISA, upon ECG evidence of LVH. In 12 patients with LVH, carteolol treatment for one year reduced mean arterial blood pressures from 120 ± 2 mm Hg to 100 ± 2 mm Hg and mean hypertrophy scores from 5.2 ± 0.6 to 2.6 ± 0.8. Therefore, ISA does not preclude the regression of ECG evidence of LVH during the treatment of hypertension. Chest 1985; 95:43-47)

The isoproterenol dose-response curve was used to assess quantitatively the degree of systemic beta-adrenoceptor blockade induced by metipranolol (Betanol) and betaxolol (Betoptic) eye drops. The study was carried out in twelve healthy volunteers, aged 22 +/- 1.4 yr. In a randomized double-blind trial, each volunteer received, on separate occasions at least one week apart, one drop in each eye of either placebo (physiological saline) or either of the ophthalmic beta-blockers. The intraocular pressure (Pio), heart rate (fc), arterial systolic (Pasys) and diastolic (Padia) pressures were measured before instillation of the eye drops after 15 to 30 min rest, and 3 h afterwards. The isoproterenol dose-response curve was studied 3 h after instillation of the drops. The CD25 (the amount of isoproterenol needed to increase fc by 25 b.min-1) was obtained by extrapolation on the least square linear regression curve. Both beta-blockers gave a significant fall in Pio compared with placebo, metipranolol more than betaxolol (p less than 0.02). There was also a significantly greater fall in fc with both metipranolol and betaxolol than with placebo. There were no changes in Pasys and Padia. CD25 was significantly increased with both beta-blocker eye drops as compared with placebo (p less than 0.05 for betaxolol; p less than 0.01 for metipranolol), but there was no difference between the two. Systemic absorption after topical application of ocular beta-blockers was thus confirmed for both metipranolol and betaxolol. However, the degree of beta-adrenoceptor blockade was weaker than that observed with other older ocular beta-blockers (timolol and carteolol).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract A radioimmunoassay for the direct measurement of carteolol, a new @-adrenoreceptor blocker, in human plasma was developed. Car- teolol was acylated to form 0-glutarylcarteolol, which was conjugated to bovine serum albumin to provide the immunogen. Antibody to car- teolol was raised in New Zealand albino rabbits. The tracer was the ra- dioiodinated derivative of 0-glutarylcarteolol-tyrosine methyl ester conjugate. The method is highly sensitive, with a lower quantifiable concentration of ∼0.4 ng of carteolol/ml using 0.1 ml of plasma, and has good specificity, with the major metabolite (8-hydroxycarteolol) showing only 0.2% cross-reactivity. It is reproducible, with relative standard de- viations from triplicate standard curves being mostly within ±8%. The method is currently being used to monitor carteolol levels in clinical samples.

o 1. 1. β-adrenoceptor mechanisms in guinea-pig taenia caecum were studied by means of a receptor-binding technique. 2. 2. Hill plots of test drugs obtained from inhibition curves were linear with slopes which were equal to 1.00. 3. 3. pKi-values of isoprenaline and desisopropylprocaterol were in agreement with those pD2-values. 4. 4. pKi-value of carteolol was in agreement with its pA2-value. 5. 5. The β-adrenoceptor is suggested to have two different sites; one can interact with the agonist and partial agonist and the other can interact with the antagonist and partial agonist.

Intraperitoneal injection of epinephrine caused a slight but significant increase in cyclic AMP in the liver and skeletal muscle in 5–10 min. Likewise, there was a significant increase in cyclic AMP in the muscle and adipose tissue 5 min after the injection of isoproterenol. However, no change was detected in the cardiac muscle. Pretreatment of rats with theophylline was so effective in enhancing responses of tissue cyclic AMP as to make it possible to detect a 2- to 3-fold increase of cyclic AMP even in the heart. The maximal increases in tissue cyclic AMP induced by 500 μg/kg of isoproterenol or epinephrine were blocked by carteolol, a new beta-adrenergic blocking agent, at doses of 10–100 μg/kg, regardless of whether or not the rats had been treated with theophylline. In contrast, neither the increase of liver cyclic AMP by glucagon nor the increase of adrenal cyclic AMP by adrenocorticotropic hormone (ACTH) was affected by this agent. Blood cyclic AMP rose sharply after isoproterenol, the maximal response attaining 20- to 30-fold of the preinjection level. Based on this tremendous increase of blood cyclic AMP, the dose of isoproterenol and carteolol required for the half-saturation of the beta-adrenergic receptor was calculated as 20–30 and 0.5 μg/kg of body wt respectively. These values are in the same order as the respective values obtained from the response of carbohydrate and lipid metabolites in blood.

Six cases of systemic reactions to topical treatment with beta-blocking eyedrops are reported, bradycardia and faintness due to an overdosage of ophthalmic timolol; decompensated heart failure one month after the prescription of carteolol eyedrops: bronchospasm after two weeks of treatment with metipranolol eyedrops; crippling Raynaud's phenomenon of otherwise unknown origin, which had begun with timolol eyedrops, continued with carteolol eyedrops and regressed after discontinuation of ophthalmic beta-blockers; aggravation of an anaphylactoid shock in a patient treated with ophthalmic timolol, and myocardial infarction possibly due to the abrupt withdrawal of timolol eyedrops. It cannot be overstressed that the rules governing the prescription of oral beta-blockers also apply to ophthalmic preparations of these drugs: respect of contra-indications, strict adherence to the dosage recommended, gradual drug withdrawal and regular supervision. Only controlled studies and long-term follow-up will be able to demonstrate differences in safety between the five beta-blockers commercialized as eyedrops in this country.

Increases in blood concentrations of glucose induced by epinephrine, of lactate induced by epinephrine and isoproterenol, and of glycerol and insulin induced by isoproterenol in rats showed graded responses dependent on the dose of the catecholamines and were blocked also progressively by increasing doses of 5-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyril hydrochloride (carteolol), a new beta-adrenergic blocking agent. The ed 50 estimated for these metabolic parameters, other than blood insulin, was 100–200 μg/kg of body wt for epinephrine and 10–20 μg/kg for isoproterenol, while the “corrected id 50” for carteolol, reflecting the dissociation constant of the antagonist-receptor complex, was 1–3 μg/kg. It is concluded that the beta-adrenergic receptors of the same character concerning the affinity to agonists and antagonists mediate the increase of blood levels of these carbohydrate and lipid intermediary metabolites, and that the affinity of carteolol is one order higher than that of isoproterenol, which in turn is ten times higher than that of epinephrine. In contrast, much higher ed 50 for isoproterenol and “corrected id 50” for carteolol were obtained when hyperinsulinemia was used as a measure of beta action, suggesting that the beta-adrenergic receptor mediating pancreatic secretion of insulin is distinct in nature from the receptors involved in the control of carbohydrate and lipid metabolism. Comparison of the potency of carteolol with those of propranolol and pindolol showed that carteolol is the most potent beta-adrenergic blocking agent.

The hypotensive mechanisms of pindolol in anesthetized and conscious rats were investigated. Pindolol caused a fall in blood pressure in anesthetized, conscious and spinal rats, though in conscious rats a higher dose of the drug was required to produce such a response. This hypotension with pindolol in anesthetized and conscious rats was markedly inhibited by pretreatment with the drug itself or other beta-adrenoceptor blocking drugs. A similar phenomenon also occurred when isoproterenol was injected intravenously in anesthetized and conscious rats. The relationship between the hypotensive actions of four beta-adrenoceptor blocking drugs in anesthetized rats and their intrinsic beta-sympathomimetic actions in isolated catecholamine-depleted tracheal preparations was determined. Order of hypotensive potencies was the same as that of their intrinsic beta-sympathomimetic action, namely, pindolol greater than carteolol greater than bufetolol in equilibrium propranolol (p less than 0.05). These results suggest that the hypotension with pindolol is mediated through a decrease in the peripheral vascular resistance due to an intrinsic beta-sympathomimetic action of the drug.

The inhibitory effect of two kinds of beta-adrenoceptor blocking drugs [propranolol: 1-100 mg/kg per day; carteolol: 0.3-30 mg/kg per day] on the development of cardiac hypertrophy was studied in young spontaneously hypertensive rats (SHR: 4 weeks old). Though neither propranolol or carteolol given for 6 weeks reduced the development of hypertension in SHR, both drugs did reduce the increase in the heart weight/body weight ratio in a dose-dependent manner. This potency of carteolol was about 300 times greater than that of propranolol. The potency of carteolol with regard to the reduction in the myocardial protein/DNA ratio was about 300 times greater than that of propranolol. The beta-blocking potency, estimated from the area under the dose-response curve (beta-blocking action) of carteolol, was also 300 times greater than that of propranolol and correlated well with the extent of the structural changes in the heart. Thus, the possibility that the degree of beta-blocking potency may strongly relate to structural changes in the heart of young SHR has to be given consideration.

A gas chromatographic method with nitrogen-selective detection has been developed that permits the sensitive and simple determination of β-adrenergic blocking drugs, including alprenolol, bufetolol, bupranolol, carteolol, nadolol, oxprenolol, pindolol and propranolol. The drugs were derivatized with n-butylboronic acid or phenylboronic acid to form their cyclic boronates. The derivatives were readily formed at room temperature, and were stable for at least 3 days. The cyclic boronates formed gave symmetrical peaks, and showed high responses with minimum detectable amounts in the range 1.5–4 pg, corresponding to 6–14>d10−16 mol/sec. Propranolol was extracted with n-hexane containing 1.5% of isoamyl alcohol from alkaline plasma by a single-extraction procedure, with bufetolol as the internal standard, and derivatized with phenylboronic acid. Accurate determinations were possible in the concentration range 1–500 ng/ml, and the minimum detectable concentration in plasma was 0.5 ng/ml, permitting the pharmacokinetic study of propranolol under therapy. Pindolol was also determined in the range 2–500 ng/ml, and the minimum detectable concentration was 1 ng/ml. These results suggest the general applicability of the method to the determination of the unchanged β-blocking drugs in plasma and other biological samples.

A HPLC method is presented for the identification and quantification in plasma and urine of beta-adrenergic receptor antagonists (betaxolol, carteolol, metipranolol, and timolol) commonly prescribed in ophthalmology. An extraction method is described using pindolol as an internal standard. An RSIL 10 micron column was used. The lower detection limits of the beta-blockers were found to be 4-27 ng/ml. This method is simple, rapid and sensitive; moreover, it allows the determination of 8 other beta-blockers.

I. The positive inotropic effect of isoproterenol was quantified in the presence of several beta-adrenergic blocking agents in ventricular strips of carp heart. 2. Isoproterenol had a concentration-dependent positive inotropic effect. The effect was markedly inhibited by propranolol and carteolol, but was extremely insensitive to atenolol. Practolol totally failed to alter the effect. 3. These results indicated that the positive inotropic effect of isoproterenol may be mediated by mostly beta-2 adrenergic receptors in ventricular strips of carp heart.

1. Isoprenaline, a beta-adrenergic full agonist, and carteolol, befunolol and BFE-55, beta-adrenergic blockers with an intrinsic sympathomimetic action, induced dose-related increases in heart rate when administered intravenously (i.v.). 2. The beta-partial agonists administered i.v. shifted a dose-heart rate increased response curve of isoprenaline, suggesting a competitive antagonism. 3. In carteolol, doses to block beta-adrenoceptors were found to be 400-1000 times lower than that to induce agonistic action. In BFE-55, doses to block beta-adrenoceptors were equal to that to induce sympathomimetic action. The difference between doses of the befunolol to produce both actions was intermediate. 4. These results suggest that there may be a difference between doses blocking beta-adrenoceptors and inducing sympathomimetic action in some beta-adrenergic partial agonists and, therefore, that there may exist beta-partial agonists which do not induce sympathomimetic action in doses blocking beta-adrenoceptors.

Primary open-angle glaucoma (POAG) is a multifactorial disease. One of the risk factors in POAG is intraocular hypertonia, but the level of intraocular pressure (IOP) does not appear to correlate with the degree of functional deficit in this disease. In fact, visual field defects have been observed in subjects with normal or only slightly elevated IOPs. Current treatment for POAG is normalization of IOP with a beta-blocker. Nevertheless, a number of studies have shown that these agents do not improve the visual fields of patients with POA(;.“.‘,“-“,“’ The actions of beta-blockers on the retinal vasculature may compromise their utility for the treatment of these patients. The purpose of the first study reported here was to determine whether a beta-blocker with intrinsic sympathomimetic activity (ISA), carteolol, would provide greater preservation of visual fields than timolol. The purpose of the second study was to determine whether a relatively specific beta, antagonist, betaxolol, was superior to timolol in visual field preservation.

We reported previously that β-blocking agents produced a sustained pressor action in anesthetized rats, and this pressor action was probably due to the blockade of the β-adrenoceptors mediating vasodilation in the vascular bed of skeletal muscle. In this study, experiments using rat hindquarters were performed to investigate further the mechanism of the pressor action. The effects of propranolol, Carteolol, practolol and acebutolol administered intraarterially to the hindquarters were studied. These β-blocking agents produced a sustained rise in perfusion pressure. The pressor actions of practolol and acebutolol were greater tnan we expected. Also effects of these β-blocking agents on changes in perfusion pressure produced by isoproterenol in rat hindquarters were studied. Inhibitory actions of practolol and acebutolol on the isoproterenol-induced depressor action in rat hindquarters were greater than in intact rats. From tnese results, it is considered that practolol and acebutolol may be able to block to a conciderable extent, not only β2-receptors in the heart, but also β2-receptors in the peripheral vascular beds in rats.