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A series of eight chiral β-blocker drugs, acebutolol, atenolol, carazolol, carteolol, carvedilol, propranolol, sotalol, and talinolol, have been enantioseparated using two single-component anionic β-CD derivatives, namely heptakis (2,3-di-O-methyl-6-sulfo)-β-CD (HDMS-β-CD) and heptakis (2,3-di-O-acetyl-6-sulfo)-β-CD (HDAS-β-CD), in aqueous CE and NACE. The influence of the nature of substituents (methyl or acetyl) in positions 2 and 3 on the CD derivatives and of the electrophoretic medium (water or methanol) on the enantioselectivity and enantiomer affinity pattern (EAP) of these structurally related compounds was systematically studied. All eight β-blockers could be enantioseparated at least partially in the four CE systems, except sotalol with HDMS-β-CD in NACE. In general, lower affinity and enantioselectivity were obtained in the presence of HDMS-β-CD compared to HDAS-β-CD. Reversals of EAPs were observed for all compounds. EAPs toward these two CDs were found to be opposite to each other in NACE for all compounds except carvedilol and in aqueous CE for atenolol, carteolol, talinolol, and sotalol. It is particularly noteworthy that opposite EAPs were also observed using the same CD derivative when the aqueous BGE was replaced with the methanolic one: for carazolol, carvedilol, and propranolol in the presence of HDMS-β-CD and for acebutolol and carvedilol with HDAS-β-CD.

To determine whether topical carteolol affects ocular blood flow, we studied effects of carteolol 2% on the ocular pulse waves in 9 normal volunteers, and analyzed the results as variations in pulsatile volume changes (PVC) for one minute (PVCm) using the Friedenwald's pressure-volume relationship. PVC means a volume for the pressure amplitude in each pulse. The pulse waves were recorded with a pneumatonometer and analyzed by a computer. The PVCm change 15 min after the carteolol instillation was evaluated with the control performed with biological salt solution in the same manner. The data showed a net increase in the PVCm of the carteolol-instilled eyes (21.3 +/- 6.4 microliters/min: mean +/- standard error, p < 0.05, paired t-test). Considering a finding that PVCm takes 50% of the total ocular blood flow, the results suggest a possible alteration in the total flow by a carteolol instillation.

A capillary electrophoresis method using carboxymethyl-beta-cyclodextrin as the chiral selector and mixture of methanol and ethanol as the organic additive was successfully developed for the simultaneous enantioseparation and determination of six beta-blockers, namely, carteolol, atenolol, sotalol, metoprolol, esmolol and propranolol in this paper. The most suitable running buffer for enantioseparation was found to be the solution of 20 mmol/L NaH(2)PO(4)-Na(2)HOP(4) (pH 5.5) containing 1.5% w/v carboxymethyl-beta-cyclodextrin, 5% v/v methanol and 5% v/v ethanol. Furthermore, field-amplified sample injection as an on-line sample stacking method was developed in order to increase the detection sensitivity. The experimental conditions for both simultaneous enantioseparation and the field-amplified sample injection method had been investigated in detail. Under the optimum conditions, the detection limits (defined as S/N=3) of this method were 0.01, 0.05, 0.05, 0.05, 0.05 and 0.5 microg /mL for (+/-) carteolol, (+/-) atenolol, (+/-) sotalol, (+/-) metoprolol, (+/-) esmolol and (+/-) propranolol, respectively, which were much lower than those of the conventional methods. The enhancement factors were greatly improved by 25-fold for the enantiomers of the beta-blockers except five-fold for (+/-) propranolol. Eventually, the proposed method has been applied for the analysis of human serum sample.

In this study, the various antiglaucoma drugs including betaxolol, timolol, levobunolol, carteolol, brimonidine, dipivefrin, dorzolamide, brinzolamide, latanoprost, unoprostone, and pilocarpine were used to investigate the effects of cellular cytotoxicity in cultured bovine corneal endothelial cells. After exposure to the drugs in three dilutions, 1/100, 1/1,000, and 1/10,000, for 100 minutes, cells were estimated based on the release assay of lactate dehydrogenase (LDH) enzyme. It was found that cellular LDH was significantly released in the medium only at 1/100 th dilution of betaxolol, brimonidine, dorzolamide, dipivefrin, latanoprost and unoprostone to 130%, 123%, 145%, 157%, 128% and 237%, respectively, compared with controls upon exposure to drugs for 100 minutes. Moreover, benzalkonium chloride preservative at the concentrations ranging from 0.001 to 0.00001mg/mL did not affect cellular LDH release in bovine corneal endothelial cells. These results indicate that high concentrations of antiglaucoma drugs may induce cytotoxicity in corneal endothelial cells.

Sublingual administration of carteolol or instillation into one eye reduces intraocular pressure (IOP) in both eyes. This suggests that carteolol absorbed systemically can reduce IOP and that the extra-ophthalmic route (e.g., the nasal route) can be an alternative method of drug administration. The authors compared the differences between ocular and nasal instillation relating to the pharmacokinetic and pharmacodynamic effects of a carteolol-ophthalmic solution on IOP and heart rate (HR) in a randomized, double-blind, crossover, placebo-controlled design in 11 healthyyoung extensive metabolizers for CYP2D6. The tmax, Cmax, and AUC0-t of carteolol (0.8 mg) instilled into the nostril were significantly higher than those into the eye (p < 0.05): tmax (h) = 0.25 (0.17-5.0),1.0 (0.17-5.0) (median value with range in the parenthesis, ocular vs. nasal); Cmax (ng/ml) = 1.33 +/- 1.57, 2.29 +/- 2.09; and AUC0-t (ng x h/ml) = 9.36 +/- 2.04, 21.13 +/- 1.58 (geometric mean +/- SD, ocular vs. nasal). The reduction of IOP after ocular instillation persisted significantly longer than that of nasal instillation (p < 0.05). The HR was significantly reduced after both ocular and nasal instillation (p < 0.05), although there were no significant differences between them. In conclusion, ocular instillation of a carteolol-ophthalmic solution has advantages over nasal instillation in controlling IOP and the potential to decrease adverse reactions due to lower plasma concentrations.

It is well known that severe gingival overgrowth (GO) is induced in patients taking certain calcium channel blockers (CCB) for the treatment of hypertension, angina pectoris, and other diseases. No case has been reported to date of severe GO induced by manidipine hydrochloride (manidipine), a second generation CCB. This case report describes severe GO induced by manidipine in a female patient (43 years old) with hypertension and Sjögren syndrome (SS). The patient was administered manidipine and carteolol hydrochloride (carteolol) as antihypertensive drugs, together with bromhexine hydrochloride for the treatment of SS.At the initial periodontal examination, probing depth (PD, average 4.83 mm), plaque control record (PCR, 84.3%), bleeding on probing (BOP, 100%), and gingival overgrowth index (GOI, 2.42) were assessed. The patient received periodontal treatment without cessation or replacement of the causative drug. Initial treatment included oral hygiene and scaling and root planing (SRP) under local anesthesia. As corrective therapy, remaining pockets were surgically removed and fixed bridges placed to establish proper occlusion.Obvious reductions in PCR (10.0%), PD (1.93 mm), GOI (0.02), and BOP (4.7%), together with a disappearance of GO, were obtained. Salivary secretion was increased after the periodontal and prosthetic treatments. Histological features were similar to those of nifedipine-induced GO.This case indicated that manidipine may act as a potent inducer of severe GO, and that conventional periodontal treatments without a major change of the causative drugs can yield satisfactory clinical responses.

Herein we present the enantioseparation of 10 cardiovascular agents and six bronchiectasis drugs including propranolol, carteolol, metoprolol, atenolol, pindolol, esmolol, bisoprolol, bevantolol, arotinolol, sotalol, clenbuterol, procaterol, bambuterol, tranterol, salbutamol and terbutaline sulfate using carboxymethyl-β-cyclodextrin (CM-β-CD) as chiral selector. To our knowledge, there is no literature about using CM-β-CD for separating carteolol, esmolol, bisoprolol, bevantolol, arotinolol, procaterol, bambuterol and tranterol. During the course of work, changes in pH, CM-β-CD concentration, buffer type and concentration were studied in relation to chiral resolution. Excellent enantiomeric separations were obtained for all 16 compounds, especially for procaterol. An impressive resolution value, up to 17.10, was obtained. In particular, most of them achieved rapid separations within 20 min. Given the fact that enantioseparation results rely on analytes' structural characters, the possible separation mechanisms were discussed. In addition, in order to obtain faster separation for propranolol enantiomers in practical application, the effective length of capillary was innovatively shortened from 45 to 30 cm. After the validation, the method was successfully applied to the enantiomeric purity determination of propranolol in the formulation of drug substances.

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 propranolol>betaxolol approximately levobetaxolol>levobunolol approximately carteolol>/=timolol>atenolol. 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.

Eleven organic solvents were tested for their suitability in the use of capillary electrophoresis (CE). In all cases, 25 mM ammonium acetate and 1 M acetic acid were used as electrolytes. Three basic therapeutical agents, propranolol, carteolol and imipramine, were used as analytes. Four solvents (2-propanol, ethylene glycol, propylene glycol, dichloromethane) were not suitable for use with CE under our conditions. Depending on the other solvents used, the analytes showed very different behavior. We observed that the epsilon/eta quotient alone is not sufficient for a characterization of the solvents. Further investigations with all the solvents as 1:1 mixtures with methanol were carried out. As a result some principal changes occurred compared to the pure solvents. Working with mixtures of different solvents proved to be advantageous because of the possibility to influence properties like high viscosity or low ionizing abilities by the addition of a suitable second solvent.

A partial beta-adrenoceptor (beta-AR) agonist will exhibit opposite agonist and antagonist activity depending on the prevailing degree of adrenergic tone or the presence of a beta-AR agonist with higher intrinsic activity. In vivo partial beta-AR agonist activity will be evident at rest with low endogenous adrenergic tone, as for example with chronotropicity (beta 1/beta 2), inotropicity (beta 1) or peripheral vasodilatation and finger tremor (beta 2). beta-AR blocking drugs which have partial agonist activity may exhibit a better therapeutic profile when used for hypertension because of maintained cardiac output without increased systemic vascular resistance, along with an improved lipid profile. In the presence of raised endogenous adrenergic tone such as exercise or an exogenous full agonist, beta-AR subtype antagonist activity will become evident in terms of effects on exercise induced heart rate (beta 1) and potassium (beta 2) responses. Reduction of exercise heart rate will occur to a lesser degree in the case of a beta-adrenoceptor blocker with partial beta 1-AR agonist activity compared with a beta-adrenoceptor blocker devoid of partial agonist activity. This may result in reduced therapeutic efficacy in the treatment of angina on effort when using beta-AR blocking drugs with partial beta 1-AR agonist activity. Effects on exercise hyperkalaemia are determined by the balance between beta 2-AR partial agonist activity and endogenous adrenergic activity. For predominantly beta 2-AR agonist such as salmeterol and salbutamol, potentiation of exercise hyperkalaemia occurs. For predominantly beta 2-AR antagonists such as carteolol, either potentiation or attenuation of exercise hyperkalaemia occurs at low and high doses respectively. beta 2-AR partial agonist activity may also be expressed as antagonism in the presence of an exogenous full agonist, as for example attenuation of fenoterol induced responses by salmeterol. Studies are required to investigate whether this phenomenon is relevant in the setting of acute severe asthma.

Since the late 1970s, topical beta-adrenergic blockers have been the drugs of choice in treating ocular hypertension and associated glaucoma. The currently available drugs are timolol, betaxolol, levobunolol, metipranolol, and carteolol. All reduce intraocular pressure by decreasing the production of aqueous humor. Although these drugs are applied locally in the eye, they may enter the general circulation and reach concentrations high enough to cause systemic effects, including alterations in heart rate and rhythm, bronchoconstriction, dyslipidemia, and central nervous system abnormalities. Interactions with other drugs may also occur. Ocular beta- blockers differ in beta 1-selectivity (betaxolol is beta 1-selective, whereas the other drugs are nonselective) and in intrinsic sympathomimetic activity (ISA) or partial agonist properties (only carteolol possesses ISA). These differences give betaxolol and carteolol potential advantages in minimizing certain side effects. The advantage of betaxolol vis-à-vis systemic side effects is more clearly established than that of carteolol. Further systematic study is needed to determine what advantages, if any, are conferred by the presence of ISA.

SUMMARY 1. When carteolol, a β-adrenergic blocker, was administered to KK-Ay/Ta Jcl mice that are obese and develop spontaneously non-insulin dependent diabetes, their increase in bodyweight was arrested from the age of 16 weeks. Since their intake of food and water was not influenced by carteolol treatment, compared with the control KK-Ay/Ta Jcl mice, abolition of the weight gain might be attributed to increased energy metabolism. 2. Non-fasting serum glucose levels in carteolol-treated mice at the age of 17 weeks were within normal range (118±4 vs 186±12 mg/dL). An intraperitoneal glucose-tolerance test revealed that the carteolol treatment markedly restored glucose metabolism; fasting plasma glucose (88±6 mg/dL) was within normal range, and immunoreactive insulin (IRI; 5.8±0.8 vs 33.3 ± 10.5 ng/mL) and plasma glucose levels at 60 min post glucose (361±44 vs 541 ±32 mg/dL) were significantly lower in carteolol-treated mice than those in the control group at the age of 20 weeks. 3. From these findings, carteolol is considered to have little effect on the growth of mice but to correct the obesity that develops after age 16 weeks, when their growth terminates. In addition, the normalization of blood glucose and marked decrease in IRI levels suggests that carteolol improves glucose tolerance by increasing the insulin sensitivity. 4. Since brown adipose tissue (BAT) is closely associated with thermogenesis and energy consumption, we tested whether carteolol may affect BAT, When the regional blood flow was measured by radioactive microspheres in rats, blood flow in BAT and white adipose tissue was markedly increased by carteolol. 5. These findings indicate that carteolol blocks β1- and β2-adrenoceptors, but may stimulate β-receptors particularly in the adipose tissue to promote lipolysis and thermogenesis, and to consume excess energy in mice. Thus, carteolol does not influence mouse growth, but may prevent obesity leading to increases in insulin sensitivity.

B antagonists eye drops are most effective for the treatment of chronic open angle glaucoma. By this way of administration they have a very good systemic bioavailability. Bronchial, and cardiovascular effects of three of these topicals: timolol, carteolol and metipranolol have been evaluated in three parallel groups of asthmatic patients. The three topics induce bronchoconstriction without significant difference between them, and lower heart rate (sometimes very intensely) whatever the B antagonist studied. From these data, it is recommended to practitioners to follow carefully the rules of administration of B blockers, even in eye drops.

The antihypertensive effect of carteolol, a new potent nonselective beta-adrenergic antagonist, was investigated in a double-blind, parallel study of 35 patients with mild-to-moderate, essential hypertension whose blood pressures were not adequately controlled with a diuretic. Patients were randomly assigned to receive placebo, carteolol 5 mg, or carteolol 20 mg once a day in addition to hydrochlorothiazide 50 mg for six weeks. Thirty-four patients completed the study: 11 patients received placebo (group 1), 12 patients received carteolol 5 mg (group 2), and 11 patients received carteolol 20 mg (group 3). After six weeks of treatment, the two groups that received carteolol had significant reductions in systolic (SBP) and diastolic (DBP) blood pressure from baseline in both the supine and standing positions. In group 2, mean SBP decreases for supine and standing positions were 11 ± 2.1 and 11 ± 1.9 mm Hg, respectively (P < .01) and 8 ± 1.2 and 9 ± 1.3 mm Hg, respectively, for DBP (P < .01); whereas in group 3, values were 8 ± 2.8 and 12 ± 3.0 mm Hg for SBP, in 5 ± 1.9 and 9 ± 3.1 mm Hg, respectively, for DBP (P < .01). The hypotensive effect was associated with slight but significant decreases in heart rate (P < .01 in group 2 and P < .05 in group 3). Reductions in SBP and DBP with the 20-mg dose were not significantly different from those with the 5-mg dose. With both carteolol regimens, the fall in mean blood pressure did not correlate with the initial level; but in the group taking the 5-mg dose, it did correlate significantly with the decrease in heart rate (r = .72, P < .01). Side effects attributable to carteolol were infrequent and did not persist during continued therapy. It is concluded that carteolol, when combined with hydrochlorothiazide, is effective in reducing blood pressure in patients with mild to moderate hypertension.

The time-course of plasma noradrenaline (NA) and adrenaline (A) concentrations and their dissipation profiles were examined concomitantly with heart rate changes after strenuous exercise in eight normal subjects receiving either placebo or carteolol, a beta-adrenoceptor blocker. Post-exercise NA concentrations declined with time in a biexponential manner, while A disappearance curves were apparently monophasic. Plasma NA concentrations and their peak value attained within 3 min after exercise were higher in the carteolol than in the placebo phase, whereas there were no significant differences in the first and second disappearance t1/2 between the two trials. The monoexponential t1/2 of A in the carteolol trial was significantly longer than in the placebo trial. Our results suggest that the dissipation profiles of catecholamines released by exercise appear to be affected by beta-adrenoceptor blockade.

5-(3-tert-Butylamino-2-hydroxy) propoxy-3, 4-dihydrocarbostyril (1, carteolol) was prepared by an acid-catalyzed cyclization of the N-pivaloylamino-ester (5), which was obtained by using organolithiation of m-pivaloylanisidine, followed by Wittig and catalytic hydrogenation reactions. The total yield of 1 obtained from m-anisidine (2) is 21%.

5-(3-tert-Butylamino-2-hydroxy) propoxy-3, 4-dihydrocarbostyril (1, carteolol) was prepared by an acid-catalyzed cyclization of the N-pivaloylamino-ester (5), which was obtained by using organolithiation of m-pivaloylanisidine, followed by Wittig and catalytic hydrogenation reactions. The total yield of 1 obtained from m-anisidine (2) is 21%.