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Beta blockers are a class of drugs commonly used to treat heart-related diseases; they are also regulated under the World Anti-Doping Agency. Tandem mass spectrometry is often used in the pharmaceutical industry, clinical analysis laboratory, and antidoping laboratory for detection and characterization of drugs and their metabolites. A deeper chemical understanding of dissociation pathways may eventually lead to an improved ability to predict tandem mass spectra of compounds based strictly on their chemical structure (or vice versa), which is especially important for characterization of unknowns such as emerging designer drugs or novel metabolites. In addition to providing insights into dissociation pathways, the use of energy-resolved breakdown curves can produce improved selectivity and lend insights into optimal fragmentation conditions for liquid chromatography-tandem mass spectrometry LC-MS/MS workflows. Here, we perform energy-resolved collision cell and multistage ion trap collision-induced dissociation-mass spectrometry (CID-MS) experiments, along with complementary density functional theory calculations, on five beta blockers (acebutolol, atenolol, bisoprolol, carteolol, and labetalol), to better understand the details of the pathways giving rise to the observed MS/MS patterns. Results from this work are contextualized within previously reported literature on these compounds. New insights into the formation of the characteristic product ion m/z 116 and the pathway leading to characteristic loss of 77 u are highlighted. We also present comparisons of breakdown curves obtained via qToF, quadrupole ion trap, and in-source CID, allowing for differences between the data to be noted and providing a step toward allowing for improved selectivity of breakdown curves to be realized on simple instruments such as single quadrupoles or ion traps., (© 2023 John Wiley & Sons, Ltd.)

Vasospastic angina (VSA) can be worsened by oral nonselective beta-blockers. Ophthalmic carteolol eye drops are nonselective beta-blockers and effective against glaucoma and ocular hypertension. Systemic effects of ophthalmic beta-blockers on VSA have not yet been reported. We herein report a case of VSA that developed after a patient started carteolol eye drops for ocular hypertension. Even though benidipine, a calcium channel blocker, was started, a VSA attack with incessant non-sustained ventricular tachycardia occurred. Once the carteolol eyedrops were discontinued, the VSA resolved. This case demonstrates that carteolol eye drops can induce life-threatening VSA.

Carteolol is a commonly-used topical medication for primary open-angle glaucoma. However, long-term and frequent ocular application of carteolol entails its residuals at low concentration in the aqueous humor for a long duration and may exert latent toxicity in the human corneal endothelial cells (HCEnCs). Here, we treated the HCEnCs in vitro with 0.0117% carteolol for 10 days. Thereafter, we removed the cartelolol and normally cultured the cells for 25 days to investigate the chronical toxicity of carteolol and the underlying mechanism. The results exhibited that 0.0117% carteolol induces senescent features in the HCEnCs, such as increased senescence-associated β-galactosidase positive rates, enlarged relative cell area and upregulated p16 INK4A and senescence-associated secretory phenotypes, including IL-1α, TGF-β1, IL-10, TNF-α, CCL-27, IL-6 and IL-8, as well as decreased Lamin B1 expression and cell viability and proliferation. Thereby, further exploration demonstrated that the carteolol activates β-arrestin-ERK-NOX4 pathway to increase reactive oxygen species (ROS) production that imposes oxidative stress on energetic metabolism causing a vicious cycle between declining ATP and increasing ROS production and downregulation of NAD + resulting in metabolic disturbance-mediated senescence of the HCEnCs. The excess ROS also impair DNA to activate the DNA damage response (DDR) pathway of ATM-p53-p21 WAF1/CIP1 with diminished poly(ADP-Ribose) polymerase (PARP) 1, a NAD + -dependent enzyme for DNA damage repair, resulting in cell cycle arrest and subsequent DDR-mediated senescence. Taken together, carteolol induces excess ROS to trigger HCEnC senescence via metabolic disturbance and DDR pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: This present study was undertaken to determine whether beta-blockers produce the cutaneous analgesic effect, comparing them with the long-acting local anesthetic bupivacaine., Methods: Using a rat model of infiltrative cutaneous analgesia, the effect of 5 beta-blockers (oxprenolol, carteolol, butaxamine, metoprolol, and acebutolol) and bupivacaine was compared and eventually combined with epinephrine., Results: Among 5 beta-blockers, oxprenolol exhibited the most potent and the longest duration of cutaneous analgesia. In dose-response studies, the rank order of efficacy (ED 50 [50% effective dose]) was bupivacaine (0.40 [0.35-0.47] μmol) > oxprenolol (2.33 [2.06-2.64] μmol) > carteolol (4.86 [4.27-5.53] μmol) ( p < 0.01). Carteolol provoked a longer duration of analgesia ( p < 0.01) than oxprenolol or bupivacaine on an equipotent basis (ED 25 , ED 50 , and ED 75 ). Adding epinephrine 1:200,000 to drug preparations (carteolol, oxprenolol, and bupivacaine) at ED 95 had a peripheral action in prolonging the duration of action., Conclusions: Oxprenolol and carteolol had greater potencies and longer durations of cutaneous analgesia than butaxamine, metoprolol, and acebutolol. Oxprenolol produced a similar duration of action when compared to bupivacaine, while carteolol had a greater duration of action than bupivacaine. Cutaneous analgesia of oxprenolol (or carteolol) plus adrenaline was greater than that of bupivacaine plus adrenaline.

The objectives of this study were to develop a sustained-release device for carteolol hydrochloride (CH) and investigate any potential difference in the intraocular distribution of this agent between the transscleral administration of the device and treatment with eyedrops. The device was formulated with photocurable resin, poly (ethyleneglycol) dimethacrylate, to fit within the curve of the rabbit eyeball. In vitro study showed that CH was released in a sustained-release manner for 2 weeks. The concentration of CH in the retina, choroid/retinal pigment epithelium, sclera, iris, and aqueous humor was determined by high-performance liquid chromatography. Transscleral administration was able to deliver CH to the posterior segment (i.e., retina and choroid/retinal pigment epithelium) rather than the anterior segment (i.e., aqueous humor), while eyedrops delivered CH only to the anterior segment. Transscleral administration could deliver CH to aqueous humor at half the concentration versus treatment with eyedrops and reduced intraocular pressure (IOP) at 1 day after implantation; however, the IOP-lowering effect was not sustained thereafter. In conclusion, transscleral drug delivery may be a useful method for the reduction of IOP. Notably, the aqueous concentration must be equal to that delivered by the eyedrops, and this approach might be preferable for drug delivery to the posterior segment of the eye., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Among benign vascular tumors of infancy, hemangiomas are the commonest, affecting approximately 5-10% of one-year-old children. They are derived from a benign proliferation of vascular endothelial cells (VECs) in the mesoderm and may arise anywhere on the body around 1-2 weeks after birth. Infantile hemangiomas (IHs) are characterized by an early proliferative phase in the first year followed by a spontaneous progressive regression within the following 5 years or longer. IH prevalence is estimated to be 5%-10% in one-year-old children and commonly affects female, Caucasian and low-birth weight infants. Although most of them spontaneously regress, approximately 10% requires treatment to prevent complications due to the site of occurrence such as bleeding, ulceration, cosmetically disfigurement, functional impairment, or life-threatening complications. For over 30 years, steroids have represented the first-line treatment for IHs, but recently topical or systemic β-blockers are increasingly being used and recognized as effective and safe. A search for "Cutaneous infantile hemangioma" [All Fields] AND "Treatment" [All Fields] was performed by using PubMed and EMBASE databases. Treatment of IHs with labeled drugs, such as oral propranolol, but also with off-label drugs, such as topical β-blockers, including topical timolol and carteolol, steroids, itraconazole or sirolimus, with a focus on formulations types and adverse events were described in our review. We also discussed the benefits of pulsed dye laser and the treatment of IHs with involvement of central nervous system, namely the PHACE and LUMBAR syndrome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor FS is currently organizing a Research Topic with the author DA., (Copyright © 2022 Macca, Altavilla, Di Bartolomeo, Irrera, Borgia, Li Pomi, Vaccaro, Squadrito, Squadrito and Vaccaro.)

Background/objective: The association between antiglaucoma medications and the development of ocular pseudopemphigoid (OPP) has been described; however, the independent risk of each medication has not been quantified., Methods: Case/non-case analyses were performed in the FDA Adverse Events Reporting System (FAERS) using data from 2010-2020 to examine the reporting odds ratio (ROR) signal for OPP for all classes of antiglaucoma medications under multiple conditions: (i) comparison to all other drugs in FAERs, (ii) comparison to other antiglaucoma medications, (iii) comparison to vehicle/hydrating eye drops with cases of OPP and (iv) comparison to vehicle/hydrating eyedrops with and without cases of OPP to control for topical irritant and preservative effects., Results: A statistically significant ROR for OPP was found for aggregate antiglaucoma medications under the first condition but not the third or fourth (i.96.97 (95% CI 52.54-178.98). The largest signal for OPP when compared to other glaucoma drugs and eye drops was seen with unoprostone (ii.68.96 (95% CI 8.35-569.50, iii.39.85 (95% CI 4.14-383.33), iv.581.67 (95% CI 49.38-6851.57) followed by carteolol (ii.32.51(95% CI 9.02-117.67), iii.10.67 (95% CI 1.77-64.13), iv.77.84 (95% CI 12.95-467.78) and betaxolol (ii.23.38 (95% CI 7.28-74.46), iii.6.94 (95% CI 1.27-38.01), iv.50.67 (95% CI 9.26-277.25). A statistically significant ROR was noted only for the beta-blockers class aggregate under conditions ii and iv., Conclusions: Our findings support an association between OPP and antiglaucoma medications; under the most stringent control for topical irritant/preservative effect by of comparison to topical eye drops, unoprostone, carteolol, betaxolol and timolol all had a significant ROR for OPP., (© 2022 Australasian College of Dermatologists.)

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.

Purpose: To evaluate the 24-h efficacy and safety of fixed combination carteolol/latanoprost (LCFC) and timolol/latanoprost (LTFC) in patients with primary open-angle glaucoma and ocular hypertension., Study Design: Prospective, randomized, crossover study METHODS: Twenty-two patients pretreated with a prostaglandin analog at baseline were randomly assigned at a 1:1 ratio to either LCFC or LTFC treatment. The patients received the assigned study drug in both eyes daily in the evening (20:00). Each treatment group crossed over after a 2-month treatment period. The 24-h curves of intraocular pressure (IOP), pulse rate, and blood pressure were evaluated. Safety was also assessed., Results: The changes in mean daytime IOP from baseline at the end of the 2-month treatment period in the LCFC and LTFC groups were  - 0.93 and  - 1.15 mmHg, respectively. The changes in peak IOP in the 2 groups were  - 0.91 and  - 0.68 mmHg, respectively. The nighttime pulse rate in the LCFC group increased; that in the LTFC group was lower at all time points. The changes in pulse rate from baseline at 22:00, 2:00, 4:00, and 6:00 differed statistically between the 2 groups. No differences in changes from baseline in systolic and diastolic blood pressures were found between the groups., Conclusion: The 24-h IOP curve of patients in the LCFC group was similar to that of the LTFC group, but on the basis of the pulse rate findings, the effect of LCFC on the cardiovascular system over 24 h was less than that of LTFC., (© 2021. Japanese Ophthalmological Society.)

Precis: In patients with normal-tension glaucoma (NTG), topical dorzolamide might enhance the vessel density (VD), topical carteolol decreased the VD in the inferior-temporal peripapillary retina, whereas topical brimonidine did not change the VD., Purpose: Topical antiglaucoma medications may improve ocular perfusion pressure or microcirculation in the optic nerve head. The study evaluated responses of retinal VD to topical carteolol, brimonidine, and dorzolamide in NTG using optical coherence tomography angiography., Patients and Methods: This is a retrospective, nonrandomized, comparative study. The study included 131 individuals (77 men, 54 women) diagnosed with NTG, without systemic medication use, who visited the glaucoma clinic of Chang Gung Memorial Hospital, Taiwan, between January 2019 and May 2020. If both eyes were diagnosed with NTG, only the right eye was included. Of these, there were 80 carteolol-treated eyes, 27 brimonidine-treated eyes, and 24 dorzolamide-treated eyes. We studied the response of optical coherence tomography angiography parameters and retinal nerve fiber layer (RNFL) thickness to drugs, 6 months after treatment., Results: In dorzolamide-treated eyes, increases in the peripapillary superficial retinal VD, especially in the superior-nasal area, were significant; however, no RNFL thickness changes were observed. In contrast, the superficial retinal VD decreased at the inferior-temporal peripapillary area, and RNFL thickness decreased in the inferior-nasal peripapillary area of carteolol-treated eyes. Finally, in brimonidine-treated eyes, changes in either VD parameters or RNFL thickness were not significant., Conclusions: Topical dorzolamide possibly enhanced the VD of the peripapillary retina in NTG eyes. On the contrary, topical carteolol possibly decreased VD in the inferior-temporal peripapillary retina. Finally, in cases treated with topical brimonidine, peripapillary microcirculation remained unchanged. The study shows preliminary results and future large-scale studies are needed to confirm findings., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Ophthalmic carteolol is often used to treat glaucoma. Elderly patients with atrial fibrillation (AF) and chronic kidney disease (CKD) are common among the super-elderly in Japan. Because these patients are exposed to polypharmacy, they are at a high-risk of adverse drug interactions. We herein report an elderly patient with CKD who suffered bradycardia shock after the combined use of carteolol eye drops and verapamil for glaucoma and paroxysmal AF. This case highlights the fact that eye drops have a similar systemic effect to oral drugs, and especially in elderly patients with polypharmacy, drug interactions can unwittingly lead to serious events.

Background: In recent years, there have been reports of contact dermatitis due to the beta-blockers that are used in the treatment of glaucoma, such as timolol, levubonolol, carteolol, or betaxolol., Case Report: A 37-year-old male patient, who was diagnosed with bilateral primary open-angle glaucoma two years ago, was in therapy with dorzolamide and a topical β-adrenergic blocker (timolol) in drops twice a day. Months later, he reported conjunctival hyperemia, stinging, and inflammation of both eyelids, followed by erythematous dermatitis, which improved upon treatment discontinuation. The patch test came back negative, but the conjunctival provocation test came back positive 48 hours later., Conclusion: Sensitization to the ophthalmic drops that are used to control glaucoma proved to be the mechanism that was causing the clinical picture of the patient. Performing a tolerance test for active anti-glaucoma agents may be helpful in improving tolerance to the medical treatment of some patients, thus, avoiding laser procedures and/or precipitated antiglaucomatous surgeries.

Carteolol is a non-selective β-adrenoceptor antagonist used for the treatment of glaucoma, and its abuse might be cytotoxic to the cornea. However, its cytotoxicity and underlying mechanisms need to be elucidated. Herein, we used an in vivo model of feline corneas and an in vitro model of human corneal endothelial cells (HCECs), respectively. In vivo results displayed that 2% carteolol (clinical dosage) could induce monolayer density decline and breaking away of feline corneal endothelial (FCE) cells. An in vitro model of HCECs that were treated dose-dependently (0.015625-2%) with carteolol for 2-28 h, resulted in morphological abnormalities, declining in cell viability and elevating plasma membrane (PM) permeability in a dose- and time- dependent manner. High-dose (0.5-2%) carteolol treatment induced necrotic characteristics with uneven distribution of chromatin, marginalization and dispersed DNA degradation, inactivated caspase-2/-8, and increased RIPK1, RIPK3, MLKL, and pMLKL expression. The results suggested that high-dose carteolol could induce necroptosis via the RIPK/MLKL pathway. While low-dose (0.015625-0.25%) carteolol induced apoptotic characteristics with chromatin condensation, typical intranucleosomal DNA laddering patterns, G 1 cell-cycle arrest, phosphatidylserine (PS) externalization, and apoptotic body formation in HCECs. Meanwhile, 0.25% carteolol treatment resulted in activated caspase-2, -3, -8, and -9, downregulation of Bcl-2 and Bcl-xL, upregulation of Bax and Bad, ΔΨm disruption, and release of cytoplasmic cytochrome c (Cyt.c) and AIF into the cytoplasm. These observations suggested that low-dose carteolol could induce apoptosis via a caspase activated and mitochondrial-dependent pathway. These results suggested that carteolol should be used carefully, as low as 0.015625% cartelol caused apoptotic cell death in HCECs in vitro ., (Copyright © 2020 Su, Zhao and Fan.)

Purpose: The purpose of the study was to evaluate influence of betaxolol, brimonidine and carteolol in the progression of the visual field defects during time at patients with normotensive glaucoma (NTG)., Materials and Methods: This study included (60 eyes of) 30 patients with NTG. First group consisted of 20 eyes of 10 patients of the average age of 58.5 years, who were treated by betaxolol. Second group also consisted of 20 eyes of 10 patients of the average age of 62.6 years and they were treated by brimonidine. Third group had the same count of the eyes and patients, the average age was 61.1 years and these patients were treated by carteolol. Diagnose of NTG was based on the comprehensive ophthalmological examination including electroretinography and visual evoked potentials. Visual fields were examined by fast threshold glaucoma test using Medmont M700 device. We compared pattern defect (PD) in the visual field for 3 years. The including criteria were: similar visual field findings at the beginning of the study, stable eye therapy (treatment was not changed during the study), uncorrected or best corrected (up to +-3 D) visual acuity of 1,0 of ETDRS, intraocular pressure between 10-15 mm Hg, if present, then compensated cardiovascular disease, no other internal or neurological disorders., Results: We didnt notice any statistically important difference of PD. The study revealed that brimonidin (p=0,99) and betaxolol (p = 0,81) had the best effect., Conclusion: Local therapy of betaxolol, brimonidine and carteolol has an essential clinical value in normotensive glaucoma. All the mentioned treatments had a protective effect on the visual field. However, local side-effects of brimonidinu are a question.

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.

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., Competing Interests: The authors declare no conflict of interest.

The 3,4-dihydro-2(1H)-quinolinone moiety is present in a number of pharmacologically active compounds. These include FDA approved drugs such as cilostazol, carteolol and aripiprazole as well as numerous experimental compounds. Compounds containing the 3,4-dihydro-2(1H)-quinolinone moiety also exhibit a variety of activities in both the peripheral and central tissues, which includes phosphodiesterase inhibition, blocking of β-adrenergic receptors, antagonism of vasopressin receptors and interaction with serotonin and dopamine receptors. Based on its versatility in drug design and action, this paper reviews the pharmacological actions of compounds containing the 3,4-dihydro-2(1H)- quinolinone scaffold with emphasis being placed on the most important and significant members of each activity class., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Aim: To investigate the intraocular pressure (IOP) of adult guinea pig eyes with rebound tonometry (RBT), and assess the effects of four distinctive topical IOP reducing medications including Carteolol, Brimonidine, Brinzolamide and Latanoprost., Methods: The IOPs of twenty-four 12-week-old guinea pigs (48 eyes) were measured every two hours in one day with RBT as baselines. All the animals were then divided into four groups (Carteolol, Brimonidine, Brinzolamide and Latanaprost groups, n =6). The IOPs were measured and compared to the baseline 1, 2, 3, 5, 7, 9, 15 and 24h after treatment., Results: The mean baseline IOP of 24 guinea pigs (48 eyes) was 10.3±0.36 mm Hg (6-13 mm Hg) and no binocular significant differences of IOPs were observed ( t =1.76, P >0.05). No significant difference of IOP in Carteolol group at each time point was observed before and after treatment ( t =1.48, P >0.05). In Brimonidine group, IOP was 2.2±1.9 mm Hg lower than the baseline after one hour ( t =3.856, P =0.003) and lasted for one hour. In Brinzolamide group, IOP was 1.4±1.1 mm Hg lower than the baseline after one hour ( t =4.53, P =0.001) and lasted for 7h and the IOP declined most at 3h. In Latanaprost group, IOP was 2.1±1.3 mm Hg lower than the baseline after one hour ( t =6.11, P =0.001) and lasted for one hour., Conclusion: The IOP of guinea pig eyes is relatively stable compared to human eyes. In four reducing IOP medications, no significant effect of Carteolol is observed. Brinzolamide has the longest duration, while the Brimonidine has the shortest duration and the maximum level of treatment.

Carteolol is a frequently used nonselective β-adrenoceptor antagonist for glaucoma and ocular hypertension treatment, and its repeated/prolonged usage might be cytotoxic to the cornea, especially the outmost human corneal epithelium (HCEP). The aim of the present study was to characterize the cytotoxicity of carteolol to HCEP and its underlying cellular and molecular mechanisms using an in vitro model of HCEP cells. After HCEP cells were treated with carteolol at concentrations varying from 2% to 0.015625%, the cytotoxicity, apoptosis-inducing effect and pro-apoptotic pathway was investigated, respectively. Our results showed that carteolol at concentrations above 0.03125% induced time- and dose-dependent growth retardation, cytopathic morphological changes and viability decline of HCEP cells. Moreover, carteolol induced G1 phase arrest, plasma membrane permeability elevation, phosphatidylserine externalization, DNA fragmentation, and apoptotic body formation of HCEP cells. Furthermore, carteolol also induced activation of caspase-9 and -3, disruption of mitochondrial transmembrane potential, up-regulation the cytoplasmic amount of cytochrome c and apoptosis-inducing factor, and up-regulation of pro-apoptotic Bax and Bad, down-regulation of anti-apoptotic Bcl-2 and Bcl-xL. In conclusion, carteolol above 1/64 of its clinical therapeutic dosage has a time- and dose-dependent cytotoxicity to HCEP cells, which is achieved by inducing apoptosis via triggering Bcl-2 family protein-mediated mitochondrial pro-apoptotic pathway., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Topically administered beta blockers are the preferred medical therapy for glaucoma. These agents reduce intraocular pressure (IOP), thereby preventing damage to the optic nerve and the subsequent loss of vision. Timolol, betaxolol, levobunolol, metipranolol, and carteolol are the topical beta blockers available in the U.S. They have similar IOP-lowering efficacy, but differ in other pharmacological properties. Topically administered beta blockers are generally well tolerated. They undergo systemic absorption, however, and can adversely affect cardiovascular and bronchopulmonary function in patients with existing diseases such as heart failure, sinus bradycardia, chronic obstructive airways disease, or asthma. Betaxolol, which is beta 1-selective, and carteolol, which has intrinsic sympathomimetic activity (ISA), may have systemic tolerability profiles superior to the traditional nonselective, non-ISA beta blockers. These hypotheses require confirmation in controlled clinical trials. Local adverse effects associated with beta blockers include stinging, burning, red eye, itching, tearing and loss of corneal sensitivity. Stinging upon instillation is a particularly frequent finding with betaxolol (up to 30% to 40% of patients). Preliminary evidence suggests that carteolol has the best local tolerability profile of these drugs.

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.

1. The effects of (+/-)-carteolol 10(-8) M to 10(-6) M, a non-selective beta-antagonist, applied cumulatively, on stimulation-evoked 3H-release at 1 Hz were studied in pulmonary arteries isolated from guinea-pigs. The guinea-pigs were subjected to either bilateral adrenalectomy, adrenalectomy followed by injections of deoxycorticosterone acetate (DOCA) and hydrocortisone, bilateral adrenodemedullation or a sham operation, and then loaded in vitro with [3H]-noradrenaline. 2. Carteolol inhibited 3H-output in arteries from sham-operated animals in a concentration-dependent manner. This inhibitory effect was not found in pulmonary arteries from animals subjected to adrenalectomy or adrenodemedullation. However, DOCA and hydrocortisone pretreatment, did not prevent the disappearance of the carteolol-induced inhibition of 3H-release. 3. Adrenalectomy and adrenodemedullation depleted or markedly reduced the endogenous contents of adrenaline in pulmonary arteries without altering the levels of dopamine and noradrenaline. 4. It is concluded that adrenaline, mainly derived from the adrenal medulla, acts as an endogenous agonist for tonically functioning prejunctional beta-adrenoceptors in guinea-pig pulmonary arteries, probably by being taken up and co-released with noradrenaline.

The effects of five beta blockers on the central nervous system of healthy subjects was studied by computerized EEG analysis. All subjects underwent continuous recording with a Holter magnetic type recorder during the experimental period. For 10 consecutive days, five groups of subjects received alternately placebo and the beta blockers acebutolol 600 mg, carteolol 20 mg, metoprolol 200 mg, pindolol 30 mg and sotalol 320 mg. EEG recordings (C4/P4, P4/02 and C3/P3, P3/01) lasting 5 min were made between 8.30 and 9.30 a.m. Subjects were at rest with eyes closed and there was no vigilance control. The signal was recorded on a magnetic tape recorder and then processed by Nicolet MED 80 system. Comparisons of absolute and relative powers and of average frequencies were then made between the different sequences and groups. The possible correlations between the changes observed in the power spectrum and the clinical, pharmacological and pharmacokinetic specific properties of each beta blocker are discussed.