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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.

The ability of 5-(3-tert-butylamino-2-hydroxy-propoxy)-3, 4-dihydro-2(1H)-quinolinone hydrochloride (carteolol hydrochloride, Endak, Endak mite) to lower the blood pressure was tested in an open clinical study on 66 patients with I-III degree essential hypertension. The results for 49 of the 66 patients were interpretable after 4 weeks, and for 39 of them after 12 weeks. Even with a single dose of 5 mg/day 33 of the patients had normalized blood pressures after 4 weeks (systolic less than 160, diastolic less than 95 mmHg); in a further 6 patients 10 mg led to normal blood pressure. For 10 patients, 4 weeks on 10 mg did not lead to an adequate response. After 12 weeks, of the 39 cases that could be checked, 19 were normalized on 5 mg, 2 on 10 mg and another 4 on 15 mg. Even 15 mg was insufficient to reduce the blood pressure of 14 of the patients adequately. Carteolol, at doses of 5-15 mg/day, caused a therapeutically acceptable lowering of the blood pressure in 60-80% of cases of essential hypertension of all 3 degrees of severity. Only 5 of the patients suffered from side-effects, none of which caused the treatment to be abandoned. A bradycardia was never observed during up to 12 weeks of continuous treatment. Tachycardias reverted to sinus rhythms of normal frequency. Blood pressure measurement by the patients themselves proved successful.

In 17 patients with coronary heart disease the influence of the beta-blocking agent 5-(3-tert-butylamino-2-hydroxy-propoxy)-3, 4-dihydro-2(1H)-quinolinone-hydrochloride) (carteolol hydrochloride, Endak, Endak mite) (0.4 mg i.v.) on heart rate, blood pressure, cardiac index, stroke volume index and pulmonary artery pressure at rest and during exercise was investigated. During exercise heart rate and cardiac index decrease significantly (p less than 0.005 and p less than 0.05, respectively). The differences in the stroke volume indices are not significant. The relationship between stroke volume index and mean pressure in the pulmonary artery shows a slight decrease after administration of carteolol at rest and a small increase of the mean pressure in the pulmonary artery during exercise. In patients with coronary heart disease left ventricular function does not change significantly at rest and during exercise after administration of carteolol.

Completing previous studies in patients with sinus bradycardia (Med. Klin. 82 [1987], 647-650) we compared metoprolol with carteolol and pindolol, pindolol with carteolol, no treatment with carteolol (in two groups) in five series of the paired comparisons of Holter-ECG each. With change from metoprolol to carteolol or pindolol (dose ratio 10:1) lowest heart rate on Holter-ECG increased by 28 or 29% without change of exercise heart rate. Direct comparison of pindolol and carteolol revealed a very similar heart rate profile, indicating equipotent beta blockade and ISA. In patients with previous beta blocker induced bradycardia, carteolol did not change a normal resting heart rate off treatment. However, in patients with spontaneous sinus bradycardia carteolol increased lowest heart rate (+14%, due to overriding ISA) and lowered exercise heart rate (-15%, due to overriding beta blockade). A beta blocker induced sinus bradycardia consistently improved with change of treatment to carteolol and pindolol. With caution carteolol and pindolol may also be used despite spontaneous sinus bradycardia.

A short survey of the chemistry of beta-blockers provides a description of the synthesis of carteolol hydrochloride (5-(3-tert-butylamino-2-hydroxy-propoxy)-3,4-dihydro-2(1H)-quinolinone- hydrochloride), the new pharmaceutically active substance of Endak and Endak mite tablets, and outlines some of its properties.

In a placebo-controlled, randomized, prospective, parallel, double-blind trial, corneal sensitivity was studied in 35 people with healthy eyes before and 1, 3, 6, 10, 15, and 30 minutes after application of carteolol 2% (20 eyes) and metipranolol 0.6% (20 eyes). Oxybuprocain 0.4% (local anesthetic, 10 eyes) served as a positive control substance, NaCl 0.9% (20 eyes) as a negative one (placebo). The test subjects assessed subjective tolerance of the test drugs on a four-step scale. Carteolol 2% did not decrease corneal sensitivity. There was no statistically significant difference between this group and the placebo group. Metipranolol 0.6% led to a decrease in corneal sensitivity of up to 14 mg (median), lasting up to 15 minutes. The decrease brought about by metipranolol 0.6% is about one-half of that caused by betaxolol 0.5%, but greater than that caused by timolol 0.5%. Oxybuprocain 0.4% causes corneal sensitivity to decrease below the measuring range of Cochet and Bonnet's esthesiometer (200 mg) for about 10 minutes. All but three eyes had returned to their initial corneal sensitivity values after 30 minutes. NaCl 0.9% eye drops do not decrease corneal sensitivity. On the contrary, a gradual increase in sensitivity (exercise effect) was found, which differed significantly from the initial value as of the 10th minute after drug application. These results confirm that it is necessary to check corneal sensitivity during topical beta-blocker therapy. "Responders," "sensitives," contact lens wearers, and patients with decreased corneal sensitivity (e.g., patients suffering from open-angle glaucoma with disk excavations, after cataract extraction or corneal transplantation) need frequent supervision.(ABSTRACT TRUNCATED AT 250 WORDS)

Publications dealing with the results of treating coronary heart disease patients with 5-(3-tert-butylamino-2-hydroxy-propoxy)-3, 4-dihydro-2(1H)-quinolinone hydrochloride (carteolol hydrochloride, Endak, Endak mite) are reviewed. They amount to 7 publications dealing with a total of 137 patients. Heart rate, blood pressure, pressure-rate product, behaviour of the S-T depression under exercise, together with the subjective declarations of the number of angina pectoris attacks and the use of nitroglycerin were used to evaluate the effectivity. The therapeutically effective doses lay between 6 and 20 mg per day. Carteolol increased the tolerance of stress by 45%, in an ergometric investigation, as compared with a placebo. The reduction of the S-T depression, typical of an anti-anginal effect, was observed in all investigations with carteolol. Carteolol reduced the increase in the arterial blood pressure under stress and lowered the raised pressure-rate product. Carteolol significantly reduced the heart rate on exercise. Tachycardiac resting rates became normal, normal rates remained unchanged. A bradycardia of less than 50 beats/min was not observed in any of the patients. Only 9 of the 137 patients suffered from side-effects and the treatment had to be terminated in just 2 cases. Pathological alterations were not revealed by the clinical laboratory investigations during any of the studies.

In an open multi-center study involving 768 patients the efficacy and tolerability of Carteolol eye drops as compared to other beta blockers were investigated. The patients started to use the new medication without a prior washout period. In patients who were well stabilized (57%), IOP either did not change when the medication was switched to Carteolol (73%) or it actually decreased. In 78% of the patients who had not responded altogether satisfactorily to the pretreatment, Carteolol eye drops lowered IOP to a tolerable level of 21 mm Hg or less without using any comedication. IOP remained hypertonic under Carteolol in only 19% of the cases. Fewer systemic and local side effects were observed under Carteolol therapy. Patients had fewer problems going upstairs. Burning after installation decreased by 25% to 2%. Even fluorescein-positive corneal findings almost completely disappeared under Carteolol.

Studies of the acute toxicity of 5-(3-tert-butylamino-2-hydroxy-propoxy)-3, 4-dihydro-2(1H)-quinolinone hydrochloride (carteolol hydrochloride, Endak, Endak mite) in various species by different modes of administration revealed comparatively slight necropsy and histological changes despite characteristic clinical features of poisoning, There were only minor discrepancies in LD50 between the different species, and no sex differences were observed. The LD50 was 2000-4000 times the therapeutic dose. Death is thought to be due to excessive enhancement of the pharmacological action of the sympathomimetic component with extreme abnormalities of blood distribution and interference with cardiac and lung function. In subchronic and chronic toxicity tests in rats no effects due to the drug were demonstrable for doses of up to 150 mg/kg. In dogs the highest dose free from side-effects was between 3 and 30 mg/kg. Above 10 times the therapeutic dose there was some increase in brown adipose tissue, but this is not thought to be of any pathological significance. No teratogenic effects were detected in experiments on mice, rats and rabbits, and no embryotoxic or fetotoxic activity was seen except for doses high enough to produce toxic effects in the mother animals. No carcinogenic properties were identified. Tests for mutagenic effects (S. typhimurium, E. coli, cytogenetic studies in rats, dominant lethal test) yielded negative results.

1. The dose-response relation and duration of action of the beta-blocking agent 5-(3-tert-butylamino-2-hydroxy-propoxy)-3,4-dihydro-2(1H)-quinolinone hydrochloride (carteolol hydrochloride, Endak, Endak mite) were investigated by means of exercise testing under randomized, double-blind conditions in two groups of healthy probands (n = 9 and n = 9, respectively). 2. The effect of 2 mg carteolol p.o. on changes in heart rate, ischemic ST-segment depression, and blood pressure was studied in 10 patients with coronary heart disease using an exercise test performed 2 h after ingestion of the drug. 3. In terms of exercise heart rate, a clear dose-response relation was demonstrated over the range of dosages (1 and 5 mg) employed. Exercise heart rate was reduced by 10% after a single dose of approximately 0.5 mg. The beta-blocking effect of 0.2 mg carteolol, however, remains unconfirmed. A dosage increase from 5 to 25 mg yields only a slight additional effect. The therapeutically attainable maximal reduction in the rise in exercise heart rate should be about 20%. 4. 24 h after a single dose of carteolol, 60-90% of the initial drug effect was still evident. 5. Resting and standing heart rate were not influenced significantly by 1, 2, 5 or 25 mg carteolol. The groups displayed a somewhat variable response. 6. 2 h after intake of 2 mg carteolol, mean ischemic ST-segment depression was reduced by somewhat more than 50%. Blood pressure at rest remained unchanged, whereas the rise in systolic blood pressure during exercise was lowered significantly. 7. In comparison with other beta-blocking agents, carteolol was effective at low dosage levels and retained considerable potency 24 h after ingestion. In many cases, once--daily administration should be adequate to yield a satisfactory clinical response.

From investigations in rats and dogs it is known that the proportion of 5-(3-tert-butylamino-2-hydroxy-propoxy)-3, 4-dihydro-2(1H)-quinolinone hydrochloride (carteolol hydrochloride, Endak, Endak mite) absorbed after oral administration is 60-80%. In dogs (as in human beings) most of it is excreted via the kidneys, but in rats biliary elimination predominates. In addition to 8-hydroxycarteolol--which also possesses pharmacological activity--the main metabolites found in dogs and rats are glucuronides of carteolol and 8-hydroxycarteolol. The elimination half-lives in dogs, rats and rabbits are between 1.2 and 3.0 h. Distribution studies point to the existence of a blood-brain barrier (rats and dogs) and a placental barrier (mice). The apparent volume of distribution measured after i.v. injection was from 2.5 to 8.5 l/kg depending on species. Passage into the milk was demonstrated in rats. Plasma protein binding is minimal. In a long-term study in dogs there was no evidence of cumulation except at the very high dosage of 200 mg/kg.

The results are summarized of 13 published investigations of the beta-blocker 5-(3-tert-butylamino-2-hydroxy-propoxy)-3, 4-dihydro-2(1H)-quinolinone hydrochloride (carteolol hydrochloride, Endak, Endak mite) with a total of 378 patients suffering from cardiac rhythm irregularities (tachycardias, extrasystoles (ES), arrhythmias). Carteolol is markedly effective against sinus tachycardia caused by functionally dependent cardiac arrhythmia, hyperthyroidism or other factors. Average daily doses of 2-10 mg produced convincing reductions in the heart rate (up to 23.5%) within two weeks. This was particularly the case for patients with initial rates of more than 100 beats/min. whereas the normal heart frequency was not affected by carteolol. The substance was also effective against beat rate increases caused by stress in patients with sinus tachycardia. Ventricular extrasystoles (63.4% efficacy) and supraventricular extrasystoles (80% efficacy) could be effectively improved. A double-blind trial of carteolol against propranolol in the treatment of extrasystoles indicates the superiority of carteolol after three weeks. Patients with frequency of 10-19 ES/min were, in particular, significantly more frequently improved. The frequency of side-effects was 4%; a discontinuation of therapy was requisite in 4 patients (1.1%).

During an open multicenter field study the new beta-blocking agent Carteolol, in 1% and 2% solution, proved to be effective and safe in the treatment of 178 patients suffering from glaucoma. On average, IOP was lowered by 5.8 to 18.7 mm Hg in nontreated and by 4.8 to 17.8 mm Hg in pretreated patients. In more than 90% of the cases both the patients and the investigators judged the treatment to be good, or better than the previous therapy. Side affects occurred in less than 3% of the cases.

The response by 14 patients with open-angle glaucoma to treatment with carteolol 1% eye drops was investigated during a study lasting up to 15 months. Statistical analysis of the data revealed that carteolol had a highly significant IOP-lowering effect in all the patients studied. The mean decrease in IOP was as much as 41% of the initial value after the first day of treatment and after one week of treatment all the IOP values were close to 16-17 mm Hg. No long-term drift was noticed during the period of the study; no patient experienced any adverse reactions which could be related to the treatment with carteolol. This study therefore confirms the results of former investigations into the IOP-lowering effect of carteolol performed on Japanese subjects and classifies carteolol as a safe antiglaucoma agent which is also effective in Caucasian patients.

The beta-blocking agent carteolol hydrochloride differs slightly from other beta-blockers by its intrinsic sympathomimetic activity. Its effect on intraocular pressure and heart rate was tested in a comparison with timolol maleate, as was subjective tolerance of it, in 28 eyes (14 subjects) with either ocular hypertension or simple chronic open-angle glaucoma. The two drugs had a similar effect on intraocular pressure; both were well tolerated subjectively. Carteolol lowered heart rate more in patients with higher heart rates, while timolol lowered it more in patients with lower heart rates.

In a planned, randomized, double blind study ocular perfusion pressures were measured before and after a 3-day regimen of 2% carteolol hydrochloride or 0.5% timolol maleate. A pressure tolerance test was also carried out. The results of this test revealed the critical pressure: it is the artificially increased intraocular pressure at which the visual function (monitored by visually evoked cortical potentials) is reduced to 20% of its initial value. The ocular perfusion pressures are affected by both drugs. They are more clearly reduced by carteolol than by timolol. The critical pressure is affected by both drugs too. After application of carteolol, the critical pressure is clearly lower than after application of timolol. The difference is statistically significant (p less than 0.05).

The compound known as 5-(3-tert-butylamino-2-hydroxy-propoxy)-3,4-dihydro-2 (1H)-quinolinone hydrochloride (carteolol hydrochloride, Endak, Endak mite) has been tested in extensive experimental pharmacological investigations both in vivo in various animal species and in appropriate in vitro systems. From the results it is clear that carteolol is a beta-adrenolytic agent with the following characteristics: 1. Carteolol exerts potent and long lasting blockade of adrenergic receptors, by oral or intravenous administration alike. 2. The effect comprises beta 1- and beta 2-receptors to an equal extent, and for this reason the drug produces haemodynamic changes and metabolic shifts in addition to cardiac effects. Carteolol can therefore be classified as a nonspecific beta-adrenergic blocker. 3. The drug displays a striking feeble local anaesthetic or nonspecific membrane-stabilizing action, probably owing to its pronounced hydrophilia. 4. There is evidence that carteolol has a relatively strong intrinsic sympathomimetic activity (ISA). This has been shown by appropriately planned investigations, and is also apparent after exceeding the doses or concentrations required for adrenolysis. 5. Carteolol causes dose-dependent changes in the electrophysiological parameters of cardiac function. In low doses or concentrations it slows heart rate and in higher doses it sometimes accelerates it. 6. Carteolol is converted - with species-specific differences - almost exclusively and to a relatively small extent into 8-hydroxycarteolol. This metabolite closely resembles the original substance and exceeds it only in ISA.

Publications dealing with investigations made with 5-(3-tert-butylamino-2-hydroxy-propoxy)-3, 4-dihydro-2(1H)-quinolinone hydrochloride (carteolol hydrochloride, Endak, Endak mite) on patients with essential hypertension, are briefly reviewed. Four controlled studies are considered in greater depth. A comparative study with pindolol indicates that the beta-receptor blocker carteolol led to a significant reduction of the elevated blood pressure of patients with essential hypertension, as did pindolol. The antihypertensive effect of carteolol, however, was seen in a significantly higher number of patients than that of pindolol (p less than 0.05). A further controlled clinical study of carteolol, this time in comparison with diuretics, also demonstrated its satisfactory antihypertensive effect. It was found that carteolol displayed a significantly greater (p less than 0.05 and p less than 0.001) effectivity in reducing the blood pressure than did previously prescribed diuretics. In another test the antihypertensive effect was established by comparison with a placebo (p less than 0.001). Moreover, a study has been made of the effect of carteolol on the renin-aldosterone system. The results established that the hypotensive effect of carteolol is not associated with an inhibition of the renin-aldosterone system.