Formulation of carteolol chitosomes for ocular delivery: formulation optimization, ex-vivo permeation, and ocular toxicity examination.

Background:Conventional delivery systems like solution and suspension are commonly used for the treatment of ocular diseases but have low corneal residence time and hence the duration of effect is limited. These drawbacks of conventional systems can be reduced by preparing bioadhesive chitosan (CH) coated noisome.Methods: Niosomes (NIM) of carteolol (CT) were developed by the thin-film hydration method and optimised by the Box-Behnken statistical design. Further, the optimised CT-NIM was coated with CH to enhance the ocular residence time . The optimised formulation was evaluated for vesicle size, entrapment efficiency, and in-vitro drug release and transcorneal permeation, histopathology, etc.Results: CT-NIM-opt showed the vesicle size and entrapment efficiency of 235 ± 3.54 nm, and 70.45 ± 0.87%, respectively. DSC spectra exhibited that CT was completely encapsulated into the CH-CT-NIM matrix. Drug release from CH-CT-NIM-opt was more sustained (68.28 ± 4.2%) than CT-NIM (75.69 ± 4.5% in 12 h) and CT solution (99.89 ± 2.8% in 4 h). The CH-CT-NIM-opt represented a strong bio-adhesion (89.76 ± 3.6%) than CT-NIM-opt (15.65 ± 3.4%). The permeation flux exhibited 1.13-fold higher permeation than CT-NIM and 3.23 fold than CT solution. The corneal hydration was found to be within the limit value. The histopathology study exhibited no structural damage to the cornea . HET-CAM results showed zero scores indicating no bleeding or haemorrhage. CH-CT-NIM-opt was found to be isotonic and exhibited good stability when stored at 4 °C for the stated duration of time.Conclusion: The above findings suggested that NIM can be a potential carrier for the delivery of CT with better ocular residence time.

Efficacy of the combination of carteolol hydrochloride + latanoprost in the treatment of glaucoma and ocular hypertension.

INTRODUCTION: The only evidence-based mechanism for prevention and treatment of glaucomatous optic neuropathy is decreasing the intraocular pressure (IOP). Prescribing multiple ocular hypotensive agents, such as the combination of carteolol and latanoprost, may synergistically improve IOP; however, doing so may increase the complexity of a medication regimen, in turn, impairing patient adherence. Fixed-combination glaucoma medications offer convenience and effectiveness. New to this class of glaucoma medication is fixed combination carteolol-latanoprost (FCCL). Area covered: This review intends to give the reader a better understanding of the efficacy of the combination of carteolol and latanoprost separately, and where FCCL fits into the vast medical arsenal of IOP drops. Furthermore, it outlines the particular pharmacologic mechanisms targeted, the pharmacokinetics, effectiveness, the advantages of fixed-combination administration, and tolerability. Expert opinion: The combination of carteolol and latanoprost, separately or in a fixed-combination, is more effective than either drug alone. Given the early stage in development of FCCL, it has yet to be determined how FCCL compares to other fixed-combination medications. However, pending further approval, fixed-combination carteolol-latanoprost may represent a reasonable alternative for a patient whose IOP is inadequately controlled on a prostaglandin analog alone and for whom a simplified combination is preferred.

Enhancement in Corneal Permeability of Dissolved Carteolol by Its Combination with Magnesium Hydroxide Nanoparticles.

We prepared magnesium hydroxide (MH) nanoparticles, and investigated their effect when combined with dissolved carteolol on the bioavailability and intraocular pressure (IOP)-reducing effect of carteolol. The carteolol was solved in saline containing additives (0.5% methylcellulose, 0.001% benzalkonium chloride, 0.5% mannitol; CRT-solution). MH nanoparticles were prepared by a bead mill method with additives. Then carteolol/MH microparticle and carteolol/MH nanoparticle fixed combinations (mCMFC and nCMFC) were prepared by mixing the CRT-solution and MH particles. The transcorneal penetration and IOP-reducing effect of carteolol was evaluated in rabbits. The mean particle size of mCMFC was 7.2 µm, and the particle size was reduced to 73.5-113.5 nm by the bead mill treatment. The MH particles in nCMFC remained in the nano size range for 8 days after preparation, and the amounts of lacrimal fluid and corneal damage were unchanged by repetitive instillation of nCMFC (twice a day for 4 weeks). The transcorneal penetration of carteolol was enhanced by the combination with MH nanoparticles, and the IOP-reducing effect of nCMFC was significantly higher than that of CRT-solution or mCMFC. In conclusion, we designed nCMFC, and showed that the high levels of dissolved carteolol can be delivered into the aqueous humor by the instillation of nCMFC. Combination with MH nanoparticles may achieve an enhancement of corneal penetration for water-soluble drugs. These findings provide significant information that can be used to design further studies aimed at developing anti-glaucoma eye drugs.

Effects of a long-acting ophthalmic formulation of carteolol containing alginic acid on the corneal epithelial barrier function and water retentive effect.

PURPOSE: Effects of a long-acting ophthalmic formulation of carteolol containing alginic acid on the corneal epithelial barrier function and its water retentive effect were investigated. METHODS: Using 10 healthy adult subjects, 2% Mikelan Ophthalmic Solution(®) (MK) was instilled in the eye once daily for 7 days (MK group) and then after a washout period of at least 28 days, 2% Mikelan LA Ophthalmic Solution(®) (MKLA) was instilled in the eye once daily for 7 days (LA group). As an index of the corneal epithelial barrier function, the fluorescein uptake was measured using Kowa FL-500. A Schirmer test was conducted to evaluate the tear dynamics. In another 10 subjects, 0.5% Timoptol(®) (TM) was instilled in the eye unilaterally twice daily for 7 days (TM group), and the tests were conducted in the same manner. RESULTS: Concerning the fluorescein uptake before and after initiation of instillation, the levels before and at 7 days after initiation of instillation were 20.7 and 26.5 ng/mL, respectively, in the LA group and 20.6 and 26.4 ng/mL, respectively, in the MK group, showing no significant difference between levels before and after initiation of instillation in either group. In the TM group, the levels were 21.4 and 65.5 ng/mL, respectively, showing a significant increase after initiation of instillation. In the Schirmer test, the values before and after initiation of instillation were 16.8 and 20.7 mm, respectively, in the LA group and 13.7 and 12.7 mm, respectively, in the MK group, showing a trend toward increase in the LA group. CONCLUSIONS: The findings suggest that the long-acting ophthalmic formulation of carteolol containing alginic acid does not affect the corneal epithelial barrier function and that it may possess a water retentive action.

Improvement of the ocular bioavailability of carteolol by ion pair.

Ocular bioavailability after instillation of carteolol was investigated by ion pair formation, taking into consideration a balance between lipophilicity and water solubility. The octanol/ water partition coefficient (PC(O/W)) and the aqueous humor concentration in rabbits after instillation of carteolol containing fatty acids having not more than 6 carbons were measured. The longer carbon chain fatty acid showed the higher PC(O/W) of carteolol. The aqueous humor concentration of carteolol increased with carbon chain length of fatty acid and was clearly correlated with logPC(O/W). The increment of counter ion also increased both the logPC(O/W) and aqueous humor concentration of carteolol. The findings suggested that the transcorneal absorption of carteolol would be designed by coordinating with quality and quantity of counter ions. The area under concentration (AUC) in aqueous humor applied by ion pair formulation containing 2% carteolol with sorbate was 2.6 times higher than that by 2% carteolol ophthalmic solution (control), whereas the AUC applied by 4% carteolol ophthalmic solution was 1.4 times higher. The plasma level after instillation of ion pair formulation was almost the same as that of 2% ophthalmic solution. The ratio of AUC (aqueous humor/ plasma) of ion pair formulation was markedly higher, as compared with those of 2% and 4% ophthalmic solution. These results showed that the ion pair formation with sorbate improved the ocular bioavailability of carteolol without enhancing systemic absorption.

Environmentally responsive ophthalmic gel formulation of carteolol hydrochloride.

Environmentally responsive gel formulation for ocular controlled delivery of carteolol hydrochloride (HCl) was developed in an attempt to improve ocular bioavailability and hence decrease its systemic absorption and side effects. The viscosity and the ability of the prepared formulations to deliver carteolol HCl in vitro and in vivo were monitored and compared with an aqueous commercial solution. The effect of polymer concentration and drug concentration on the in vitro release of carteolol HCl was examined. Gelrite formulations showed pseudoplastic behavior with thixotropic characteristics and the viscosity of the prepared systems increased as the concentration of the polymer increased. At fixed drug concentrations, as the Gelrite concentration increased, the drug release decreased. At fixed polymer concentrations, as the drug concentration increased the release of drug increased. Gelrite formulation (0.4% w/w) containing 1% drug showed significantly improved bioavailability compared with the commercial aqueous solution (Arteoptic 1%). The developed in situ gel formulation showed potential for use as delivery systems with superior ocular bioavailability of carteolol HCl.

Comparison of carteolol plasmatic levels after repeated instillations of long-acting and regular formulations of carteolol 2% in glaucoma patients.

BACKGROUND: A new long-acting (LA) formulation of carteolol 2% instilled once daily has been shown to provide a therapeutic effect similar to that of the regular formulation of carteolol 2% instilled twice daily. This study was designed to test whether the new formulation reduces the systemic delivery of carteolol. METHODS: In this double-masked, randomised, intra-subject comparative study, 23 patients with bilateral primary open-angle glaucoma or bilateral ocular hypertension received sequentially, according to the randomised order of administration, each of the 2 following treatments: carteolol 2% LA once daily for 2 months and carteolol 2% regular twice daily for 2 months. Treatments were instilled in both eyes throughout the study period. At the end of each period of treatment, blood samples were taken immediately before the last morning instillation (residual time), then 30 min, 1 h, 2 h and 4 h after this instillation in order to measure the carteolol plasma concentrations. RESULTS: The mean values of maximal plasma concentration (C(max)), residual level and area under the curve obtained following carteolol 2% LA treatment were significantly lower than the values obtained after carteolol 2% regular treatment (mean+/-SD): C(max) (ng/ml): 1.72+/-0.85 versus 3.64+/-3.65; residual level (ng/ml): 0.70+/-0.58 versus 1.80+/-0.84; area under the curve (ng/mlxh): 5.50+/-2.66 versus 10.27+/-5.46. Regarding safety, two drug-related, non-serious adverse events were reported in the LA group: one case of moderate, superficial, punctate keratitis and one case of "bitter taste in the throat." Both treatments appeared to be well tolerated. CONCLUSIONS: The data from this study showed that the systemic delivery of carteolol is lower for the once-daily LA formulation than for the regular twice-daily formulation. Consequently, long-acting carteolol eye-drops should reduce the risk of beta-blocking systemic side effects.

Pharmacokinetic and pharmacodynamic differences between ocular and nasal instillation of carteolol on intraocular pressure and heart rate in Japanese men with high CYP2D6 activity.

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.

Ocular drug delivery using 20-kHz ultrasound.

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

Alginic acid effect on carteolol ocular pharmacokinetics in the pigmented rabbit.

The effect of alginic acid addition to 1% or 2% carteolol solutions on the ocular penetration of the drug has been evaluated in the pigmented rabbit. During single dose studies, an increase in bioavailability ranging from 40% to 60% was observed in the aqueous humor and in the iris-ciliary body. During repeated dose studies, this increased ocular bioavailability of carteolol in the presence of alginic acid led to an equivalent concentration in the target tissue, although the dosage was only once a day compared with twice a day for the usual carteolol eyedrops. 14C-carteolol distribution studies demonstrated the binding of carteolol in pigmented ocular tissues. Thus, the presence of alginic acid as a new excipient supports a possible decrease in dosage regimen, while retaining sufficient ocular bioavailability to lower intraocular pressure.

Ocular hypotensive efficacy and safety of once daily carteolol alginate.

BACKGROUND/AIM: Carteolol is a beta adrenoceptor antagonist used topically to reduce intraocular pressure, typically twice daily. In an effort to provide a once daily dosing regimen, carteolol was formulated with 1% alginic acid. The objective of this study was to evaluate the efficacy and safety of carteolol alginate solution in comparison with standard carteolol solution. METHODS: This was a double masked, parallel group, multicentre study. Patients with ocular hypertension or open angle glaucoma (n=235) were randomly assigned to receive either carteolol alginate once daily [corrected] or standard carteolol solution, twice daily. The masking was maintained through the use of a vehicle in the evening for the alginate group. Patients were evaluated at baseline, 15, 60, and 120 days. RESULTS: At 0900 (presumed trough) on day 60, mean reductions in intraocular pressure (IOP) from baseline were 6.09 (SD 2.97) and 6.09 (3.18) mm Hg for the standard carteolol and alginate, respectively. At 1100 (presumed peak), mean reductions were 6.51 (2.53) and 6.47 (2.76) mm Hg, respectively. Results were similar at other times (day 15 and day 120). The most common side effect was transient stinging on instillation of drops, which did not differ significantly between groups. There were no differences of note in other ocular or systemic signs or symptoms. CONCLUSION: The new alginate formulation of carteolol 2% given once daily was as effective as standard carteolol 2% given twice daily with no meaningful differences regarding safety.

A new long acting ophthalmic formulation of carteolol containing alginic acid.

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

Pharmacokinetic and pharmacodynamic interactions among haloperidol, carteolol hydrochloride and biperiden hydrochloride.

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

Pharmacokinetics of topical beta-adrenergic antagonists in rabbit aqueous humor evaluated with the microdialysis method.

The microdialysis method was used to evaluate the pharmacokinetics of the beta-adrenergic antagonists carteolol and timolol and the new ophthalmic solution WP-934 in rabbit aqueous humor, following instillation. A probe with a microdialysis membrane (length, 5 mm; diameter, 0.2 mm) was implanted in the anterior chamber of the pigmented rabbit and perfused with Ringer's solution. Twenty microliters of 0.5% timolol maleate (0.5% Timoptol(R)), 2% carteolol hydrochloride (2% Mikelan(R)), or a novel preparation of 0.5% timolol maleate (WP-934) that gels after instillation were then instilled. The concentrations of these drugs in dialysates were measured using high-performance liquid chromatography and an electrochemical detection system. In vitro relative recovery of the membrane with timolol and carteolol was approximately 17.5% and 21. 6%, respectively. Timolol and carteolol levels in aqueous humor increased rapidly after instillation of Timoptol and Mikelan and reached maximal levels (Cmax) within 60 minutes. The Cmax of carteolol (4.25 microg ml-1) was lower than that of timolol (5.52 microg ml-1), suggesting that the corneal permeability of timolol is higher than that of carteolol. After instillation of WP-934, the Cmax of timolol (12.32 microg ml-1) was 2.2-fold higher than that after instillation of Timoptol. However, t1/2 values of beta-adrenergic antagonists after instillation of the three preparations were not significantly different. These data suggest that the microdialysis technique is useful for continuous monitoring of aqueous levels of beta-blockers and for analysis of their pharmacokinetic parameters while requiring much fewer animals than conventional sampling with paracentesis.

Intracerebral penetration of carteolol hydrochloride in rats.

To elucidate the penetrability of carteolol, a beta-adrenoceptor antagonist (beta-blocker) into the brain of rats, intracerebral and serum concentrations of the compound were determined in male rats receiving single or repetitive oral administration of carteolol hydrochloride at 30 mg/kg. The time-course of the intracerebral concentration of carteolol following single IV administration of the compound at 10 and 30 mg/kg was also studied in male rats. A high-performance liquid chromatography method was used to determine the intracerebral and serum concentrations. Following single oral dosing, the intracerebral concentration of carteolol reached a maximum of 0.074 microgram/g at 2 h postdosing and declined with a half-life of 3.7 h, and the Cmax and AUC of carteolol in the brain were 12.5% and 19.8% of those in serum. The intracerebral and serum concentrations of carteolol were determined in male rats receiving repetitive oral dosing of the compound once daily for 7 days. The concentration of carteolol in the brain and serum at 1 h postdosing varied within a range of 0.059-0.091 microgram/g and 0.321-0.443 microgram/ml, respectively, throughout the dosing period, showing no changes in the penetrability of the compound into the brain due to repeated dosing. The concentration of carteolol in the brain and serum increased in a dose-dependent manner in rats receiving a single IV administration of the compound. The elimination half-life of carteolol in the serum and brain was 0.6-0.8 h and 1.3-1.7 h, respectively, in rats following single IV dosing of the compound. The half-life in the brain was about twice as long as that in the serum. The brain to serum concentration ratio was 0.306:0.499. From the above results, it was concluded that carteolol is distributed from the circulation to the brain with low penetrability.

In-situ ocular absorption of ophthalmic beta-blockers through ocular membranes in albino rabbits.

Ocular membranes have been characterized by in-situ absorption of the ophthalmic beta-blockers carteolol (hydrophilic) and timolol and befunolol (lipophilic) using a cylindrical cell. After introduction of drug solution into the cell on the cornea, sclera (bulbar conjunctival and scleral layer) or palpebral conjunctiva, the disappearance of the drug from the cell was determined as in-situ absorption. The ophthalmic drugs disappeared from the conjunctival and scleral membranes although disappearance from the cornea was hardly observed. The conjunctival membrane showed the highest permeability. Lipophilic drugs were more permeable than hydrophilic. In-situ apparent permeability coefficients of the ophthalmic drugs through the conjunctiva and sclera correlated with the lipophilicity of drugs. A high drug concentration in the aqueous humor was observed after corneal application. There is a relationship between concentration in the aqueous humor was observed after corneal application. There is a relationship between concentrations of drugs in the aqueous humor and previously reported in-vitro apparent permeability coefficients of the drugs in the cornea. This in-situ method using a cylindrical cell is a useful method of investigating the ocular absorption of ophthalmic drugs.

Determination of the beta-blocker carteolol in human plasma by a sensitive gas chromatographic-negative-ion chemical ionization high-resolution mass spectrometric method.

A specific and sensitive gas chromatographic-high-resolution mass spectrometric method for the determination of 5-(3-tert.-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyril (carteolol), which is a beta-blocker giving depression of intraocular pressure, was developed to elucidate the pharmacokinetics of its ophthalmic application. Carteolol has been determined by high-performance liquid chromatography but with less satisfactory sensitivity. Carteolol was derivatized with pentafluorobenzoyl (PFB) amide followed by dimethylethylsilyl (DMES) ether, resulting in a high negative-ion current. The PFB-DMES derivative of carteolol was determined by the gas chromatography-negative-ion chemical ionization mass spectrometry (GC-NICI-MS) using selected-ion monitoring at low and high mass spectrometric resolution. the detection limit was less than 100 fg when the fragment ion was monitored at m/z 552.2067 in the NICI mode using methane as a reagent gas. The quantification limit of carteolol in human plasma with this method was less than 30 pg/ml. The proposed GC-MS method is considered to have sufficient specificity and sensitivity to study the pharmacokinetics of carteolol used as an ophthalmic solution.

Ocular distribution of carteolol after single and repeated ocular instillation in pigmented rabbits.

To investigate the distribution and elimination of carteolol in pigmented rabbits, 14C-carteolol eye drops were instilled singly and repeatedly. After single ocular instillation, the radioactivity in the iris and ciliary body reached maximum levels at 24 h. The elimination rate of pigmented tissues decreased at a half-life of approximately 15 days. The concentration of radioactivity in pigmented tissues increased markedly by repeating the ocular instillation and reached a maximum after the 80th repeated instillation. The concentration of radioactivity at 1 h after 80th instillation was 63.7 times that in the iris, 61.1 times that in the ciliary body and 17.2 times that in the retina & choroid after single instillation. No accumulation of radioactivity was found in other ocular tissues.

Poly(epsilon-caprolactone) nanocapsules in carteolol ophthalmic delivery.

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.

Effects of nanomolar to submillimolar carteolol on noradrenaline release in the absence and presence of uptake1 and uptake2 blockers in guinea pig pulmonary arteries.

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.