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Catecholamines play a major role during initiation and propagation of myocardial ischemia (MI). Therefore their influence on the size of an acute regional MI was investigated in isolated, coronary ligated rabbit hearts during electrical pacing at different rates (Langendorff, constant pressure: 70 cm H2O, Tyrode solution, Ca2+ 1.8 mmol/l). MI was quantified from NADH-surface-fluorescence-photography. After coronary occlusion the stimulation-rate was increased stepwise from 180 beats/min to 300/min. Experiments were performed in hearts of control and reserpinized rabbits (reserpine 7.0 mg/kg i.p. 24 h before preparation). Hearts of control animals were submitted to beta-blockade by propranolol (10(-8) mol/l) or the partial agonists pindolol (10(-6) mol/l) or carteolol (10(-6) mol/l). In untreated control hearts MI was significantly enlarged with increasing heart-rate (p0.05). At 300/min MI was doubled as compared to that observed at 180/min. In hearts of reserpinized animals this effect was absent (p0.05). Moreover, in control hearts the growth of MI could be prevented by beta-blockade with propranolol, pindolol or carteolol (p0.05), however, these hearts became insufficient as indicated by an increase in left ventricular enddiastolic pressure. Therefore we conclude that the pacing-rate dependent growth of MI seems not to be primarily related to myocardial left ventricular pressure nor to the heart rate. Nevertheless the growth of MI is strictly related to the release of catecholamines and might be caused by oxygen free radicals generated from noradrenaline by autoxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether there is an age-related difference in circadian blood pressure changes after administration of a beta-adrenergic blocker, 24-hour ambulatory blood pressure was measured before and after administration of long-acting carteolol, a beta-blocker with intrinsic sympathomimetic activity, in 9 younger and 13 older hypertensive patients. Ambulatory blood pressure was measured noninvasively using an ambulatory blood pressure monitor every 30 minutes for 24 hours before and 8 weeks after a once-daily administration of 15 mg of carteolol. Systolic and diastolic blood pressure in the office significantly decreased in both groups after 8 weeks of carteolol treatment. The whole-day systolic and diastolic blood pressures also fell significantly after carteolol treatment in both groups. Carteolol reduced systolic and diastolic blood pressures during the day in both groups. However, no reduction was observed in nighttime systolic blood pressure in either group, although nighttime diastolic blood pressure tended to decrease in the younger group (P = 0.051). The pulse rate during the night significantly increased in both groups, although no change was observed during the day in either group. We conclude that the antihypertensive effect of carteolol on the circadian blood pressure pattern in younger and older hypertensive patients is comparable. Carteolol reduced only daytime blood pressure while hardly affecting the nighttime blood pressure in both groups.

In order to increase the ocular absorption of carteolol, this antiglaucomatous drug was incorporated into either nanoparticles (NP) or nanocapsules (NC). The polymer used was poly(epsilon-caprolactone) (PCL). The dosage forms were tested on intraocular hypertensive-induced rabbits. Results are presented as the chronological variations of the intraocular pressure (IOP) in comparison with the commercial aqueous solution (Carteol eye drops). The therapeutic results (decrease in IOP) were much more pronounced with carteolol incorporated into the colloidal carriers than with the commercial eye drops. Further, NC displayed a better effect than NP because the drug was entrapped in the oily core of the carrier, thus more readily available to the eye. The incorporation of the drug into nanocapsules produced a decline in the cardiovascular side effects in comparison with aqueous eye drops, thus showing that the undesired noncorneal absorption was reduced. In conclusion, colloidal suspension made of poly(epsilon-caprolactone) could offer a good opportunity for ophthalmic delivery of drugs.

Liposomes are small lipid vesicles capable of trapping beta-blockers such as carteolol within their bilayer structure, the advantage being improved drug action, prolonged action time, and a reduction in drug concentration. In a prospective, randomized double-blind trial, carteolol 2%, liposomes (frozen and thawed multilamellar vesicles, FAT-MLVs), or carteolol 2% suspended with FAT-MLVs was applied to 25 eyes of 25 patients per group in a single 20 microliters dose. Intraocular pressure was measured for 3 days. A significant reduction in the IOP was observed in the patient groups receiving carteolol and carteolol suspended with liposomes. Moreover, improved action and prolongation of drug action was noted in the carteolol/MLV group as compared to carteolol treatment alone. Hence, carteolol 2% is suitable for reduction of IOP, but a reduction of drug concentration can be achieved by suspension with liposomes, thus reducing the side effects.

Effects of nanomolar to submillimolar carteolol, a non-selective beta-antagonist, on the evoked release at 1 Hz and the spontaneous release in the absence and presence of uptake1 and uptake2 blockers were studied in pulmonary arteries, isolated from guinea pigs, and then preloaded with [3H]noradrenaline. dl-Carteolol at 10(-8), 10(-7) and 10(-6) M applied at the increasing concentrations inhibited the evoked [3H]-release in untreated arteries and in desipramine and corticosterone-treated arteries. The spontaneous [3H]-release slightly but significantly increased or tended to increase in untreated arteries. dl-Carteolol at 10(-5) and 10(-4) M clearly and concentration-dependently increased the spontaneous [3H]-release in untreated and cocaine-treated arteries. This increase was markedly inhibited by further pretreatment with normetanephrine. The evoked [3H]-release was not altered by dl-carteolol at 10(-5) M, but increased at 10(-4) M. This increase was not modified by cocaine and by cocaine and normetanephrine. d-Carteolol at 10(-5) and 10(-4) M produced effects similar to those of dl-carteolol. Nanomolar to micromolar dl-carteolol inhibits the evoked [3H]-release, which supports our previous conclusion that this inhibition is due to blockade of tonically functioning presynaptic beta 2-adrenoceptors. Carteolol at the higher concentrations seems to become a substrate for an uptake2 mechanism and to produce an unknown sympathomimetic activity in guinea pig pulmonary arteries.

The influences of Carteolol and Timolol eye drops on intraocular pressure (IOP) and visual fields were compared in a multi-center, double-masked, prospective study. Two-hundred and forty eyes of 120 patients were initially included in the study, and 142 eyes of 72 patients fulfilled all the criteria for final statistical analysis. Both drugs significantly reduced IOP. The visual fields in both treatment groups did not change during one year of treatment. In both groups some patients improved slightly, and others deteriorated slightly. This indicates that locally applied beta-blockers may efficiently stop further progression of visual field defects in cases with increased IOP and early visual field damage. There was no difference between Carteolol and Timolol in this regard. The side effects were minimal, and there were no differences in their frequency or intensity in the two treatment groups.

Effects of timolol (0.5%) and carteolol (2%) on ocular pulsatile blood flow (PBF) were studied in healthy adult volunteers. PBF was measured with the BFA system, analyzing the ocular pressure waves. Each drug was instilled in one eye and PBF was measured in both eyes before and fifteen minutes after the instillation. In each drug, the PBF change between the two measurements was evaluated with a control study, which was performed in the same manner with physiological saline solution. In the non-instilled eyes, both timolol (n = 6) and carteolol (n = 9) had no significant change on PBF. In the instilled eyes, timolol (n = 6) caused no significant change, whereas carteolol (n = 9) increased PBF significantly. The range of the BFA system measurement error was within 4.7 +/- 2.4 microliters/min (P = 95%). Taking the error into account in each instilled eye, timolol (n = 6) increased PBF in 3 eyes and decreased it in 3 eyes, while carteolol (n = 9) increased PBF in 7 eyes, did not change it in one eye and decreased it in one eye. It is thought the effect of carteolol to increase PBF may be explained by endothelium-dependent relaxing factor (EDRF).

Effects of carteolol on ERG b-wave amplitude were investigated in dark adapted isolated perfused cat eyes. Carteolol enhanced ERG b-waves with both strong stimuli that reflect the function of both the rod and cone systems, and weak stimuli that reflect the function of the rod system. These observations suggest the following two ideas i.e.: 1. Carteolol increases the flow in retinal vessels of perfusate. or 2. Carteolol has interaction with retinal beta-adrenergic receptors related to the origin of the ERG b-wave. It is likely that both participate in the intrinsic sympathomimetic activity and the release activity of the endothelium derived relaxing factor of carteolol.

The authors studied the ocular hypotensive effect of 8-hydroxycarteolol, a main metabolite of carteolol in normal human eyes, after topical administration in a double masked randomized study. After instillation of 0.01%, 0.1%, 0.5% and 1% ophthalmic solutions of 8-hydroxycarteolol, statistically significant reduction of intraocular pressure was observed 8 and 24 hours after administration (p less than 0.05). It's maximum reduction of intraocular pressure, 1.6 +/- 0.5 mmHg was produced 24 hours after treatment by 0.1% solution. However, diurnal variation of IOP did not show a statistically significant difference.

The effect of topical carteolol 1%, a beta-adrenergic blocker with intrinsic sympathomimetic activity, on the retinal circulation was investigated in 15 normal subjects using laser Doppler velocimetry and monochromatic fundus photography. In a double-masked randomized design, one eye received one drop of carteolol 1% and the fellow eye one drop of placebo. Vessel diameter, maximum erythrocyte velocity, and volumetric blood flow rate were determined in a major temporal vein of each eye just before instillation of the drops and then 120 min later. No significant changes in heart rate or mean brachial artery blood pressure were detected after treatment. Intraocular pressure decreased by 28% in the carteolol-treated eye (P less than 0.0001) and by 15% in the placebo-treated eye (P less than 0.001). No significant changes in vessel diameter, maximum erythrocyte velocity, and volumetric blood flow rate were observed in the carteolol-treated eyes (0.3%, 4.3%, and 3.6%, respectively) or the placebo-treated eyes (0.5%, 5.8%, and 6.7%, respectively).

Topical beta-blockers reduce the intraocular pressure (IOP) by blockade of sympathetic nerve endings in the ciliary epithelium causing a fall in aqueous humour production. Two types of topical beta-blockers are available for use in glaucoma: nonselective, which block both beta 1- and beta 2-adrenoceptors; and cardioselective, which block only beta 1-receptors. Of the beta-Blockers commercially available, timolol, levobunolol, metipranolol and carteolol are nonselective, and betaxolol is cardioselective. Twice-daily timolol is probably the most effective agent in lowering IOP, although levobunolol is equally effective and can be used once daily with little difference in effect. Carteolol is used twice daily and any theoretical advantage in diminished side effects conferred by its partial beta-agonist activity compared with timolol has not been fully substantiated. Metipranolol is effective twice daily and does not have partial beta-agonist activity. Betaxolol has an effect comparable to timolol in lowering IOP, but is less effective in some patients. beta-Blockers can be used with other antiglaucoma medications, but their combined action with epinephrine (adrenaline) is suspect, particularly in the case of the nonselective beta-blockers, and the effect should be assessed in patients on an individual basis. Local stinging can be a problem in some patients with betaxolol. The most serious side effects of beta-blockers are the exacerbation of chronic obstructive airways disease with nonselective agents and the precipitation of bronchospasm in some patients. Betaxolol seems relatively free of adverse respiratory effects, although this may be dose-related and extreme caution should still be exercised in patients with any history of respiratory illness. Because of the lower risk of precipitating side effects, betaxolol is probably the beta-blocker of first choice for use in glaucoma; timolol or levobunolol are reserved for patients who do not respond satisfactorily to betaxolol and are quite free of respiratory disease.

1. The aims of this study were to investigate the partial agonist profile of carteolol and evaluate methodology for differentiating relative beta 1 and beta 2 partial agonist activity (PAA) in vivo. 2. Eight normal subjects received single oral doses of carteolol 10 mg, 30 mg and 60 mg; nadolol 40 mg; pindolol 30 mg and placebo, given in a single-blind, randomised crossover design. 3. beta 1-PAA was demonstrated with carteolol by dose-related increases in resting heart rate and systolic blood pressure, and a plateau in the dose-response curve for attenuation of exercise tachycardia. beta 2-PAA with carteolol was evidenced by a dose-related increase in resting finger tremor and progressive attenuation of exercise-induced hyperkalaemia. beta 2-adrenoceptor antagonism was shown by attenuation of terbutaline induced hypokalaemic, chronotropic and finger tremor responses. 4. Carteolol behaved as a non-selective beta-adrenoceptor antagonist with both beta 1 and beta 2-PAA components. In the standard clinical dose range of 10-30 mg, its in vivo PAA effects were relatively beta 1-selective. Thus at low doses, there appeared to be a dissociation between selectivity of antagonist and partial agonist activity. 5. Attenuation of exercise hyperkalaemia appears to be a novel and sensitive method for the evaluation of beta 2-PAA in vivo.

Liposomes are used as carries providing a prolonged and improved drug action. They are capable of trapping beta-blockers such as Carteolol. In a randomized prospective double-blind clinical trial, Carteolol 2% suspended with frozen and thawed multivesicular large vesicles (FAT-MLV), FAT-MLV, and Carteolol 2% were applied to normal (slightly cataracterous) eyes and immediately after extracapsular cataract extraction or phakoemulsification with implantation of a posterior chamber lens in a standard procedure. Twenty-five patients were included in each group. Intraocular pressure (IOP) was measured for 3 days using applanation tonometry. In the normal eyes, a significant reduction of IOP was found for the patients receiving Carteolol and Carteolol MLV suspension. Moreover, an improved action and a prolongation of drug action was registered in the Carteolol/MLV group as compared to Carteolol treatment alone. After cataract operation, the control groups showed a significant increase in IOP. Carteolol produced a constant level of IOP but the Carteolol/MLV suspension showed a stronger decrease after ECCE and a still stronger decrease after phakoemulsification. Hence, Carteolol is suitable for the reduction of IOP but a Carteolol/MLV suspension is more effective, providing the possibility of a single application of a low-dose beta-blocker after cataract extraction with posterior chamber lens implantation.

A combination of nifedipine (40 mg twice daily) plus carteolol (10 mg twice daily) was compared with nifedipine monotherapy in ten patients with essential hypertension. Ambulatory blood pressure (BP) monitoring over 24 hours and treadmill exercise testing were performed before treatment with nifedipine (but after the placebo period), after four weeks of nifedipine treatment, and after four weeks of nifedipine+carteolol combination therapy. At the end of nifedipine monotherapy, 24-hour average ambulatory BP, minimum ambulatory BP during sleep, maximum ambulatory BP, and casual BP all decreased significantly (P less than 0.01). However, the standard deviation (SD) of the ambulatory BP was not affected. The change in systolic BP response to treadmill exercise increased. After a four-week period of nifedipine+carteolol combination therapy, average ambulatory BP and maximum ambulatory BP were further decreased (P less than 0.01). The SD of the ambulatory BP and the change in BP response to exercise were significantly decreased (P less than 0.01), but the minimum ambulatory BP was not affected. These findings suggest that nifedipine and carteolol differ in their influence on diurnal BP variation and on exercise-induced BP elevation. Carteolol may mainly attenuate stress-induced BP elevation and have little influence on nocturnal BP decline. In contrast, nifedipine may affect the BP profile uniformly over the entire day. Nifedipine+carteolol combination therapy may be superior to nifedipine monotherapy because carteolol has a minimal effect on nocturnal BP and decreases stress-induced BP elevation.

Carteolol is a relatively potent nonselective beta-adrenoceptor antagonist with partial agonist activity. It is used topically to reduce elevated intraocular pressure (IOP) in patients with glaucoma or ocular hypertension. Twice-daily ocular administration of carteolol 1 or 2% lowers IOP by approximately 32% on average in patients with these conditions, an efficacy equivalent to that of timolol 0.25 or 0.5%. Carteolol eyedrops lack local anaesthetic activity, appear to cause less local irritation than timolol, and produce less pronounced decreases in heart rate or dyspnoea, possibly due to partial agonist activity. The latter activity may also improve retinal perfusion. Thus, although additional comparative trials are needed to accurately assess the precise place of carteolol in therapy, this drug offers a useful alternative to timolol in the management of conditions associated with a raised IOP, and may have advantages in older patients with regard to its tolerability profile, although careful monitoring is still wise.

Carteolol is a nonselective beta-blocker with intrinsic sympathomimetic activity (I.S.A.). A multicenter trial was started to check if the theoretical advantages of this new drug could also be confirmed in a clinical setting. The intraocular pressure (I.O.P.), the visual field and the adverse reactions were evaluated at day 8, 60, 360 and 960. The results of this study demonstrate that carteolol effectively lowers the I.O.P. with minimal adverse side effects in previously treated as well as untreated patients.

We studied the effects of chronic administration of beta-adrenoceptor antagonists with and without intrinsic sympathomimetic activity (ISA): carteolol (with ISA) and propranolol (without ISA), respectively, on the heart of spontaneously hypertensive rat (SHR) and Wistar Kyoto rat (WKY). Six-week-old SHRs and WKYs were orally given carteolol or propranolol for ten weeks. The heart rate was reduced in propranolol-treated SHR, but not in carteolol-treated ones. In WKY, carteolol-treatment increased the heart rate. The number and affinities of beta-adrenoceptors were analyzed using [3H]dihydroalprenolol as a ligand. Propranolol at 30 mg/kg increased the number of cardiac beta-adrenoceptors in both SHR and WKY. In contrast, 10 mg/kg carteolol significantly decreased the number of cardiac beta-adrenoceptors in SHR, but not in WKY. These data indicate that carteolol, a beta-adrenoceptor antagonist with ISA, does not cause up-regulation of the number of cardiac beta-adrenoceptors in the rat and suggest that this fact is related to a possible lack of "rebound phenomena" after sudden discontinuation of chronic carteolol-therapy in humans.

It was reported that 8-Hydroxycarteolol (8-OH CA), the major metabolite of carteolol hydroxychloride (CA), has a slightly different pharmacological effect from CA. We studied the reduction of intraocular pressure (IOP) on a single eyedrop application of 8-OH CA in albino and pigmented rabbit eyes. To determine the characteristic of 8-OH CA and CA, we investigated the binding ability of these drugs to synthetic melanin. In the present study, topically applied 2% CA did not significantly decrease IOP in albino and pigmented rabbit eyes. Topically applied 0.01, 0.05, 0.1 and 1.0% 8-OH CA significantly decreased the IOP of albino rabbit as did 0.1 and 1.0% 8-OH to pigmented rabbit eyes. The maximum reduction of IOP was 3.5 +/- 0.33 mmHg (mean +/- SEM) in albino rabbit and 3.0 +/- 0.45 mmHg (mean +/- SEM) in pigmented rabbit. Maximum IOP reduction was obtained after 30 min. from topical application in albino rabbit, but in pigmented rabbit after 1 hour or later. Our binding studies to melanin show that the melanin binding ability is less for 8-OH CA than for CA at any concentrations. These results may indicate that lower concentrations of topically applied 8-OH CA profoundly reduce IOP compared to CA, and 8-OH CA has less effect on melanin than CA.

The stereoselectivities of β-adrenergic partial agonists for the high affinity binding site of β-adrenoceptors in the rabbit ciliary body and the guinea-pig taenia caeci were studied. The pA2 values of the S-(−)-isomers of befunolol and carteolol against S-(−)-isoprenaline, which were calculated from the shift of each concentration–response curve in increasing cyclic AMP levels, were significantly larger than those of the R-(+)-isomers in the guinea-pig taenia caeci, while the pA2 values of the S-(−)-isomers were not significantly larger than those of the R-(+)-isomers in the rabbit ciliary body. The pKi values determined from the binding experiments were in good agreement with the pA2 values from the increases in cyclic AMP levels. These results suggest that the high affinity binding site of β-adrenoceptors in the guinea-pig taenia caeci may be able to discriminate stereoselectively between the R-(+)- and S-(−)-isomers, while in the rabbit ciliary body there is no stereoselectivity between the two enantiomers.Key words: stereoselectivity, β-adrenoceptor, partial agonist, rabbit ciliary body, guinea-pig taenia caeci.

In a randomized study in 26 elderly patients with mild essential hypertension, acute effects of alpha- and beta-adrenoceptor blockade on plasma ANP levels were examined at rest and during ergometric exercise. Plasma ANP level and LVEF were measured before and after administration of prazosin (an alpha 1-adrenergic blocker), atenolol (a cardioselective beta-adrenergic blocker), or carteolol (a nonselective beta-adrenergic blocker). Plasma ANP level was increased by exercise. Carteolol and atenolol increased plasma ANP levels at rest and during exercise, but the effect of atenolol was not statistically significant. Prazosin significantly suppressed the ANP values at rest and during exercise. The LVEF was increased by prazosin and decreased by beta-blockers, especially by carteolol. Multivariate regression analysis showed that LVEF was the most significant predictor of the plasma ANP level at maximal exercise; the resting blood pressure and heart rate were not predictors of this value. The results showed that single administrations of an alpha-blocker and a nonselective beta-blocker had opposite effects on the plasma ANP level both at rest and during exercise in elderly patients with mild essential hypertension. The observed difference in the ANP response seems to be related to changes in left ventricular function rather than changes in blood pressure or heart rate.

1. Fischer male rats were trained to avoid shock in a shuttle box. After this procedure, a small ECG transmitter was incorporated under the skin of thorax. 2. In saline group, when in the shuttle box heart rate significantly increased, and decreased while exposed to the buzzer. 3. When beta-blocker (carteolol, pindolol, propranolol) was injected, heart rate did not increase after the rat was put in the shuttle box, but decreased after exposed to the buzzer. Change in heart rate was not shown when diazepam was injected. 4. These results indicated that diazepam is more effective than beta-blocker in terms of instability of heart rate in conditioned rats.

Carteolol, a nonselective beta-adrenergic antagonist with intrinsic sympathomimetic activity, was compared in 1% and 2% topical solutions with 0.5% timolol in 105 patients with primary open-angle glaucoma. In this double-masked, randomized 3-month trial, all three preparations significantly lowered intraocular pressure throughout the study, with no significant differences being observed. There were also no significant differences among the three preparations with regard to ocular or systemic adverse reactions, including heart rate and blood pressure.

The effects of cumulatively applied doses (10(-8) M, 10(-7) M and 10(-6) M) of dl-carteolol, a nonselective beta-antagonist, on stimulation-evoked [3H] release at 5 Hz for 40 sec, were studied in renal arteries isolated from prehypertensive 4 weeks old spontaneously hypertensive rats unexposed and exposed to swimming stress for 1 hr, and then loaded with [3H]-noradrenaline. Carteolol, at 10(-8) M and 10(-7) M, produced no effect and at 10(-6) M it slightly inhibited the evoked [3H] release in the arteries from control spontaneously hypertensive rats. Carteolol, 10(-8) M to 10(-6) M, consistently inhibited the evoked [3H] release in renal arteries from spontaneously hypertensive rats exposed to stress and this inhibition differed from no effect, at 10(-8) M and 10(-7) M, and was greater than that at 10(-6) M in the arteries from control spontaneously hypertensive rats. Swimming stress increased the endogenous contents of adrenaline and dopamine in renal arteries without altering the level of noradrenaline. In conclusion, adrenaline appears to act as an endogenous agonist for tonically functioning presynaptic beta-adrenoceptors in renal arteries from prehypertensive young spontaneously hypertensive rats. Moreover, during and after a stressful situation, increased adrenaline appears to participate in further augmentation of vascular noradrenergic neurotransmission via further activation of these adrenoceptors to facilitate the release of noradrenaline.

Effects of carteolol on norepinephrine (NE) release were studied at 2 Hz mainly in rat hypothalamic slices. Isoproterenol at 1 and 10 nM concentration-dependently facilitated NE release. Isoproterenol (10 nM)-induced facilitation was antagonized by 1 and 10 nM dl-carteolol, but not antagonized by 1 nM d-carteolol. dl-Carteolol alone at 1 nM to 10 microM did not inhibit NE release. In brainstem slices, 10 nM isoproterenol also facilitated NE release, and this facilitation tended to be antagonized by 1 nM dl-carteolol. Nanomolar concentrations of carteolol stereoselectively antagonized isoproterenol-induced facilitation of NE release via presynaptic beta-adrenoceptors in rat hypothalamic slices.

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.

A randomized double-blind study of aqueous humor flow and intraocular pressure measurements before and four hours after instillation of placebo and beta-blocker eyedrops, was carried out in 40 hypertensive patients. The treated and non-treated patients either did or didn't show an optic disc excavation and a visual field defect. Hypertensive patients with a previous tension treatment will stop therapy on a 3-week period up to an increase of their own ocular tension value greater than or equal to 3 mmHg. The intraocular pressure statistically decreased of 20.8% four hours after topical placebo, the aqueous humor flow remaining unchanged. In this study, timolol eyedrops induced a greater decrease of the aqueous humor flow (39%), followed equally by betaxolol (23.8%) and carteolol (20.42%). Timolol and betaxolol eyedrops equally induced a significant decrease of the intraocular pressure. There was no effect of carteolol on the intraocular pressure. The outflow facility was independent of the instilled beta-blocker eyedrop.

The preventive effects of carteolol, a β-adrenoceptor antagonist, on secondary lesions were pathophysiologically examined in stroke-prone spontaneously hypertensive rats (SHRSP) from 8 to 30 weeks of age. Carteolol was added to the drinking water in doses of 0.005% (8 to 18 weeks of age) to 0.01% (19 to 30 weeks of age) (3.8 and 6.0 mg/kg/d, respectively). These animals gained significantly more weight than the untreated control SHRSP, and their heart rate was reduced from 14 weeks of age. Suppression of blood pressure rise was not definite, however, histology revealed prevention of the development or aggravation of secondary hypertension-related lesions, such as myocardial fibrosis, proliferative arteriolitis, necrotic arteriolitis and renal glomerular lesions. A decrease in nonesterified fatty acids in the serum was evident. Thus, carteolol has cardiac as well as renal protective effects, in the SHRSP.

We report the resolution of racemic (+/-)-1 with (R)-(+)-methylbenzyl isocianate and the synthesis of (R)-1 and (S)-1 via Sharpless chiral epoxidation. The enantio- and tissue-selectivity of such enantiomers, as beta- and alpha-adrenoceptor antagonists, were studied. Compound 1, while confirming the potent beta-blocking activity, displayed a modest enantio-selectivity towards beta 1- and beta 2-adrenoceptors. All the compounds displayed no activity as alpha-adrenoceptor blockers.

1. Effects of temperatures (0, 10 and 32 degrees C) on the bindings of beta-adrenergic partial agonists, befunolol and carteolol, with beta-adrenoceptors were studied using the microsomal fractions from the guinea-pig taenia caecum. 2. The affinities of befunolol and carteolol to the low affinity binding site were higher at low temperatures, whereas those to the high affinity binding site were not influenced by change in temperature. 3. The interactions of the low affinity binding site with befunolol and carteolol decreased both enthalpy and entropy. The interactions of both the drugs with the high affinity binding site increased only entropy. 4. These results support our view that beta-adrenoceptors contain two different affinity binding sites and that the interactions of beta-adrenergic partial agonists with the low affinity binding site induce the beta-adrenomimetic action, whereas the competitive antagonism by the beta-partial agonists and beta-adrenoceptor blockers is due to their ability to compete with beta-stimulant for the high affinity binding site.

We have tested the effects of carteolol and 8-hydroxycarteolol on cAMP generation in S49 lymphoma and BC3H1 smooth muscle-like cells. Carteolol was a high affinity β-adrenoceptor antagonist in both systems but did not stimulate cAMP accumulation. The metabolite 8-hydroxycarteolol also was a high affinity antagonist. In contrast to its parent compound, however, it possessed an agonistic component which was considerably stronger than that of other β-adrenoceptor blockers with intrinsic sympathomimetic activity, e.g. dichloroisoprenaline, pindolol, or celiprolol. These results suggest that metabolites can possess different pharmacodynamic properties in terms of β-adrenoceptor interaction relative to parent compounds.

In a placebo-controlled, randomized, prospective, parallel, double-masked trail we study corneal sensitivity before and after application of 2% carteolol (20 eyes) and 0.6% metipranolol (20 eyes). 2% carteolol does not decrease corneal sensitivity (no significant difference to the placebo group). 0.6% metipranolol leads to a decrease of corneal sensitivity up to 14 mg/S (median), lasting up to 15 minutes. The local anesthetic effect is an important parameter for the subjective compatibility.

1. 1. The beta-adrenomimetic and beta-adrenolytic activities of S(−) and R(+) isomers of carteolol, a beta-adrenergic partial agonist (a beta-adrenoceptor blocker with intrinsic sympathomimetic action) were tested in the guinea-pig taenia caecum. 2. 2. The beta-adrenoceptor blocking activities (pA2 values) of S(−) and R(+) isomers of carteolol were significantly larger than the corresponding beta-adrenomimetic activities (pD2 values), supporting our views that beta-adrenoceptors contain two different binding sites; high and low affinity sites. 3. 3. In beta-adrenoceptor blocking action S(−) carteolol was about 10 times as potent as R(+) carteolol, while beta-adrenomimetic action of S(−) carteolol was about 2 times as potent as that of R(+) carteolol. Further, intrinsic activity for S(−) carteolol was slightly but significantly larger than that for R(+) carteolol. 4. 4. These results suggest that the binding site for competitive antagonism between S(−) isoprenaline and S(−), R(+) and RS(±) carteolol is more stereoselective than the binding site to induce beta-adrenomimetic action.

PURPOSE To analyze whether rebamipide (REB) and carteolol hydrochloride (CH) protect against UVB-induced corneal damage in mice. METHODS BALB/c mice topically pretreated with REB (1 and 10 mM) or CH (1, 10, and 100 mM) were exposed to ultraviolet (UV) B light at 416 micro W/cm(2). To evaluate corneal damage, mire irregularity was graded, and the haze index was estimated by using digitized corneal images. The formation of oxidized DNA in the corneal epithelium resulting from UVB exposure was estimated by using quantitative immunohistochemistry for 8-hydroxy-2-deoxyguanosine (8OHdG index). To analyze the mechanism of cytoprotection by REB and CH against UVB-induced cell damage, the UV absorption spectrum in these agents was evaluated by spectrophotometry, and their hydroxyl radical scavenging effect was evaluated by the electron spin resonance (ESR) spin trapping technique with Fenton system hydroxy radical generation. RESULTS Seventy-two hours after UVB exposure, the severity of mire irregularity, haze index, and 8OHdG index were significantly lower in mice pretreated with 10 mM (P < 0.05, P < 0.05, and P < 0.01, respectively) of REB and in mice pretreated with 10 mM (P < 0.05, P < 0.01, and P < 0.01, respectively) and 100 mM (P < 0.01, P < 0.01, and P < 0.01, respectively) of CH compared with mice treated with vehicle. The absorption spectrum of REB overlapped with the UVB wavelength, and that of CH overlapped partially. The ESR spin signal corresponding to the hydroxyl radical was reduced by the addition of REB or CH. CONCLUSIONS REB and CH attenuate UVB-induced corneal damage, which may be partly responsible for their sunscreening and hydroxyl radical scavenging effects.

79-YEAR-OLD man was seen by us with sudden onset of unilateral ocular pain and redness earlier the same day. Vision in the affected eye had been blurred in the morning but had progressively cleared throughout the day. There was no history of trauma and no significant medical history. On examination, visual acuity was 6/12 corrected in the affected eye and 6/6 in the other eye. Biomicroscopic examination revealed a 1-mm hyphema, intraocular pressure of 31 mm Hg, and nodular structures on the pupillary margin (Figure). A small bleed from one of these lesions was observed. The fellow eye showed similar iris lesions but no hyphema and normal intraocular pressure. The results of funduscopy were normal in both eyes. A diagnosis of spontaneous hyphema with secondary raised intraocular pressure was made, and topical treatment with atropine, betamethasone, and carteolol hydrochloride was initiated. Two days later, the intraocular pressure had decreased to 12 mm Hg. Use of the mydriatic and -adrenergic blocking agent was discontinued and the steroids tapered. COMMENT The nodular lesions on the pupillary margin are iris vascular tufts, also known as capillary hemangioma or microhemangioma of the iris. These lesions occur as single or multiple, usually bilateral, vascular tufts 15 to 150 µm in size. 1,2 Fluorescein angiography demonstrates leakage from these vascular anomalies. 2,3 Histopathologic examination shows an aggregate of small, thin-walled vessels at the pupillary margin and mild chronic inflammatory cell infiltration in the iris. 3 The origin is unknown. Most patients are older than 50 years and have no systemic disease, but in some series an association with diabetes mellitus and myotonic dystrophy has been described. 2,4,5 No sex or racial predilection has been reported. The natural course of this pathologic condition is benign; the lesions rarely bleed, and recurrent hemorrhages

As further classes of antihypertensive agents become available, more attention is being directed toward the ancillary pharmacological activities of the drugs, such as metabolic effects, fl-Adrenoceptor blockers are known to produce different effects on serum lipids, depending on their pharmacological characteristics [1, 2]; for example, non-cardioselective ffblockers without intrinsic sympathomimetic activity (ISA) have been reported to raise triglycerides and to lower HDL-cholesterol [3, 4], while cardioselective flz-blockers show less of this adverse effect [5], and/3-blockers with ISA appear to cause the least alteration in serum lipids [6]. Nevertheless, the precise reasons why/3-blockers with ISA have a less unfavourable effect on lipid metabolism than those without ISA remains unclear. The present study was designed to assess whether a fl-blocker with partial selective ~-adrenoceptor agonism would have any advantageous metabolic effects when compared to a convectional/3-blocker with ISA. The metabolic effects of carteolol (10 mg, once daily), a/3-blocker with potent intrinsic sympathomimetic activity [7, 8], and dilevalol (100 mg, once daily), a/3-blocker with fl2-selective ISA [9], have been in compared 9 patients with untreated mild-to-moderate, otherwise uncomplicated, essential hypertension (WHO Classes I and II) in a randomised, two-way, cross-over trial, following a 2-week run-in control period. Blood samples for measurement of serum lipids, creatine phosphokinase (CK), uric acid and glycosylated haemoglobin Ale (HbAlc), an indicator of glycaemic control, were obtained from each of the patients after a 12-h overnight fast at the end of the 2-week run-in and of 6-week fixed maintenance periods of carteolol and dilevalol. The results are summarized in Table 1. Six-week oral monotherapy with carteolol and dilevalol significantly lowered (P

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.

Purpose Among ocular hypotensive agents, intrinsic sympathomimetic activity (ISA) is unique to carteolol hydrochloride. This study was conducted to evaluate the central nervous system (CNS) and plasma lipid profiles associated with timolol maleate and carteolol hydrochloride in postmenopausal black women with primary open-angle glaucoma (POAG) or ocular hypertension. Methods One hundred subjects met the inclusion and exclusion criteria for this randomized, double-masked, multicenter, parallel-group study. After completion of informed consent and complete ophthalmic examination, eligible patients entered a washout period, during which no topical ophthalmic medications were used. Blood samples were obtained for hematology and blood chemistry evaluations. Vital signs, ocular symptoms, Symptom Checklist-90-R (SCL-90-R) evaluation, intraocular pressure (IOP) measurements, and slit-lamp examinations were performed before randomization to treatment with either topical carteolol hydrochloride 1.0% or topical timolol maleate 0.5%. Patients received active medications twice daily and were monitored at 4 weeks and 12 weeks. At the conclusion of treatment, vital signs, ocular symptoms, SCL-90-R evaluation, IOP, slit-lamp examinations, and blood samples were obtained. Results Compared with baseline, high-density lipoprotein (HDL) cholesterol was significantly decreased (worsened) in the timolol group but did not change significantly in the carteolol group. The between-group difference was statistically significant. Total cholesterol to HDL ratio significantly increased (worsened) in the timolol group compared with baseline but did not change in the carteolol group. The difference between groups was statistically significant. No significant differences were observed between groups in SCL-90-R results for either somatization or depression. Conclusions These results suggest that topical carteolol hydrochloride may have a more favorable blood lipid profile than topical timolol maleate in postmenopausal black women with POAG or ocular hypertension. Carteolol and timolol appear to have similar CNS side effect profiles.

PURPOSE To determine whether two topical beta-blockers, timolol and carteolol, differently affect plasma lipids and lipoproteins in normolipidemic Japanese patients with glaucoma. PATIENTS AND METHODS Thirty-three normolipidemic patients with primary open-angle glaucoma or ocular hypertension were randomly allocated to and completed 16 weeks of bilateral treatment with 0.5% timolol, 1.0% carteolol, or 2.0% carteolol twice daily in a three-center, prospective study. Patients using any drugs affecting plasma lipids or with a history of beta-blocker use of hyperlipoproteinemia were excluded. Fasting blood lipids and lipoproteins, including total cholesterol, high-density lipoprotein cholesterol, triglyceride, and apoproteins, were measured three times before therapy was initiated. These measurements were repeated every 4 weeks during the treatment period. RESULTS The level of high-density lipoprotein cholesterol significantly decreased in the timolol treatment group but did not change in the carteolol treatment groups. The ratio of total cholesterol minus high-density lipoprotein cholesterol to high-density lipoprotein cholesterol increased in the timolol treatment group. CONCLUSIONS Topical beta-blockers do affect plasma lipids in Japanese patients with glaucoma. The effects of timolol are greater than those of carteolol.