Different concentrations of betaxolol switch cell fate between necroptosis, apoptosis, and senescence in human corneal stromal cells.

Betaxolol is commonly used to manage glaucoma in clinical practice. However, its long-term use may damage the cornea. Thus, the cytotoxicity and mechanisms of betaxolol in human corneal stromal cells (HCSCs) warrant further study. In this study, we used in vitro HCSCs and in vivo rabbit corneal models to investigate betaxolol cytotoxic effects and mechanism of action. At near-clinical concentrations (0.28% and 0.14%), betaxolol inhibited caspase-8 activity, activated receptor-interacting protein kinase (RIPK)1, RIPK3, and mixed-spectrum kinase-like domain (MLKL), and phosphorylated MLKL to induce necroptosis in HCSCs. Similarly, moderate concentrations of betaxolol (0.07%-0.0175%) activated caspase-8 to trigger the exogenous apoptotic pathway. Through the intrinsic apoptotic pathway, betaxolol upregulated the expression of Bcl-2 family apoptotic proteins Bax and Bad and downregulated that of anti-apoptotic proteins Bcl-2 and Bcl-xL. This subsequently disrupted the mitochondrial membrane potential and cytoplasmic transfer of cytochrome c and apoptosis-inducing factor, activated caspase-9, and induced apoptosis in HCSCs. Furthermore, continuous treatment with low betaxolol concentrations (0.00875%) for three generations of HCSCs prevented apoptosis by promoting the expression of Bcl-xL and suppressing that of Bax. However, its toxic effects initiated cellular senescence by increasing reactive oxygen species, leading to the disruption of energy metabolism and DNA damage. Finally, clinical concentrations of betaxolol had a pro-apoptotic effect on rabbit corneal stromal cells in vivo. These results suggest that betaxolol induces cytotoxicity in a concentration-dependent manner in HCSCs, and that caspase-8 and Bcl-2 family proteins may be critical switches in the conversion of different HCSC death mechanisms.

Paternal methamphetamine exposure induces higher sensitivity to methamphetamine in male offspring through driving ADRB1 on CaMKII-positive neurons in mPFC.

Paternal abuse of drugs, such as methamphetamine (METH), elevates the risk of developing addiction in subsequent generations, however, its underlying molecular mechanism remains poorly understood. Male adult mice (F0) were exposed to METH for 30 days, followed by mating with naïve female mice to create the first-generation mice (F1). When growing to adulthood, F1 were subjected to conditioned place preference (CPP) test. Subthreshold dose of METH (sd-METH), insufficient to induce CPP normally, were used in F1. Selective antagonist (betaxolol) for ß1-adrenergic receptor (ADRB1) or its knocking-down virus were administrated into mPFC to regulate ADRB1 function and expression on CaMKII-positive neurons. METH-sired male F1 acquired sd-METH-induced CPP, indicating that paternal METH exposure induce higher sensitivity to METH in male F1. Compared with saline (SAL)-sired male F1, CaMKII-positive neuronal activity was normal without sd-METH, but strongly evoked after sd-METH treatment in METH-sired male F1 during adulthood. METH-sired male F1 had higher ADRB1 levels without sd-METH, which was kept at higher levels after sd-METH treatment in mPFC. Either inhibiting ADRB1 function with betaxolol, or knocking-down ADRB1 level on CaMKII-positive neurons (ADRB1CaMKII) with virus transfection efficiently suppressed sd-METH -evoked mPFC activation, and ultimately blocked sd-METH-induced CPP in METH-sired male F1. In the process, the p-ERK1/2 and ΔFosB may be potential subsequent signals of mPFC ADRB1CaMKII. The mPFC ADRB1CaMKII mediates paternal METH exposure-induced higher sensitivity to drug addiction in male offspring, raising a promising pharmacological target for predicting or treating transgenerational addiction.

Betaxolol as a Potent Inhibitor of NDM-1-Positive E. coli That Synergistically Enhances the Anti-Inflammatory Effect in Combination with Meropenem.

With significant human and economic losses, increasing bacterial resistance is a serious global threat to human life. Due to their high efficacy, broad spectrum, and cost-effectiveness, beta-lactams are widely used in the clinical management of bacterial infection. The emergence and wide spread of New Delhi metallo-ß-lactamase (NDM-1), which can effectively inactivate ß-lactams, has posed a challenge in the design of effective new antimicrobial treatments. Medicine repurposing is now an important tool in the development of new alternative medicines. We present a known glaucoma therapeutic, betaxolol (BET), which with a 50% inhibitory concentration (IC50) of 19.3 ± 0.9 µM significantly inhibits the hydrolytic activity of the NDM-1 enzyme and may represent a potential NDM-1 enzyme inhibitor. BET combined with meropenem (MEM) showed bactericidal synergism in vitro. The efficacy of BET was further evaluated against systemic bacterial infections in BALB/c mice. The results showed that BET+MEM decreased the numbers of leukocytes and inflammatory factors in peripheral blood, as well as the organ bacterial load and pathological damage. Molecular docking and kinetic simulations showed that BET can form hydrogen bonds and hydrophobic interactions directly with key amino acid residues in the NDM-1 active site. Thus, we demonstrated that BET inhibited NDM-1 by competitively binding to it and that it can be developed in combination with MEM as a new therapy for the management of infections caused by medicine-resistant bacteria.

The role of beta- and alpha-adrenergic receptors on alcohol drinking.

Alcohol Use Disorders (AUD) is characterized by compulsion-like alcohol drinking (CLAD), where intake despite negative consequences can be a major clinical obstacle. With few treatment options available for AUD, there is a significant need for novel therapies. The noradrenergic system is an important hub for regulating stress responses and maladaptive drives for alcohol. Studies have shown that drugs targeting α1 adrenenergic receptors (ARs) may represent a pharmacological treatment for pathological drinking. However, the involvement of ß ARs for treating human drinking has received scant investigation, and thus we sought to provide pre-clinical validation for possible AR utility for CLAD by analyzing whether ß AR antagonists propranolol (ß1/2), betaxolol (ß1), and ICI, 118,551 (ß2) impacted CLAD and alcohol-only drinking (AOD) in male Wistar rats. We found that the highest dose of propranolol tested systemically (10 mg/kg) reduced alcohol drinking, while 5 mg/kg propranolol reduced drinking with a trend to impact CLAD more than AOD, and with no effects of 2.5 mg/kg. Betaxolol (2.5 mg/kg) also decreased drinking, while ICI 118.551 had no effects. Also, while AR compounds might have utility for AUD, they can also lead to undesirable side effects. Here, a combination of ineffective doses of propranolol and prazosin reduced both CLAD and AOD. Finally, we investigated the effect of propranolol and betaxolol in two brain areas related to pathological drinking, the anterior insula (aINS) and medial prefrontal cortex (mPFC). Surprisingly, propranolol (1-10 µg) in aINS or mPFC did not affect CLAD or AOD. Together, our findings provide new pharmacological insights into noradrenergic regulation of alcohol consumption, which may inform AUD therapy.

Physicochemical properties and micro-interaction between micro-nanoparticles and anterior corneal multilayer biological interface film for improving drug delivery efficacy: the transformation of tear film turnover mode.

Recently, various novel drug delivery systems have been developed to overcome ocular barriers in order to improve drug efficacy. We have previously reported that montmorillonite (MT) microspheres (MPs) and solid lipid nanoparticles (SLNs) loaded with the anti-glaucoma drug betaxolol hydrochloride (BHC) exhibited sustained drug release and thus intraocular pressure (IOP) lowering effects. Here, we investigated the effect of physicochemical particle parameters on the micro-interactions with tear film mucins and corneal epithelial cells. Results showed that the MT-BHC SLNs and MT-BHC MPs eye drops significantly prolonged the precorneal retention time due to their higher viscosity and lower surface tension and contact angle compared with the BHC solution, with MT-BHC MPs exhibiting the longest retention due to their stronger hydrophobic surface. The cumulative release of MT-BHC SLNs and MT-BHC MPs was up to 87.78% and 80.43% after 12 h, respectively. Tear elimination pharmacokinetics study further confirmed that the prolonged precorneal retention time of the formulations was due to the micro-interaction between the positively charged formulations and the negatively charged tear film mucins. Moreover, the area under the IOP reduction curve (AUC) of MT-BHC SLNs and MT-BHC MPs was 1.4 and 2.5 times that of the BHC solution. Accordingly, the MT-BHC MPs also exhibit the most consistent and long-lasting IOP-lowering effect. Ocular irritation experiments showed no significant toxicity of either. Taken together, MT MPs may have the potential for more effective glaucoma treatment.

The Isoleucine at Position 118 in Transmembrane 2 Is Responsible for the Selectivity of Xamoterol, Nebivolol, and ICI89406 for the Human ß1-Adrenoceptor.

Known off-target interactions frequently cause predictable drug side-effects (e.g., ß1-antagonists used for heart disease, risk ß2-mediated bronchospasm). Computer-aided drug design would improve if the structural basis of existing drug selectivity was understood. A mutagenesis approach determined the ligand-amino acid interactions required for ß1-selective affinity of xamoterol and nebivolol, followed by computer-based modeling to provide possible structural explanations. 3H-CGP12177 whole cell binding was conducted in Chinese hamster ovary cells stably expressing human ß1, ß2, and chimeric ß1/ß2-adrenoceptors (ARs). Single point mutations were investigated in transiently transfected cells. Modeling studies involved docking ligands into three-dimensional receptor structures and performing molecular dynamics simulations, comparing interaction frequencies between apo and holo structures of ß1 and ß2-ARs. From these observations, an ICI89406 derivative was investigated that gave further insights into selectivity. Stable cell line studies determined that transmembrane 2 was crucial for the ß1-selective affinity of xamoterol and nebivolol. Single point mutations determined that the ß1-AR isoleucine (I118) rather than the ß2 histidine (H93) explained selectivity. Studies of other ß1-ligands found I118 was important for ICI89406 selective affinity but not that for betaxolol, bisoprolol, or esmolol. Modeling studies suggested that the interaction energies and solvation of ß1-I118 and ß2-H93 are factors determining selectivity of xamoterol and ICI89406. ICI89406 without its phenyl group loses its high ß1-AR affinity, resulting in the same affinity as for the ß2-AR. The human ß1-AR residue I118 is crucial for the ß1-selective affinity of xamoterol, nebivolol, and ICI89406 but not all ß1-selective compounds. SIGNIFICANCE STATEMENT: Some ligands have selective binding affinity for the human ß1 versus the ß2-adrenoceptor; however, the molecular/structural reason for this is not known. The transmembrane 2 residue isoleucine I118 is responsible for the selective ß1-binding of xamoterol, nebivolol, and ICI89406 but does not explain the selective ß1-binding of betaxolol, bisoprolol, or esmolol. Understanding the structural basis of selectivity is important to improve computer-aided ligand design, and targeting I118 in ß1-adrenoceptors is likely to increase ß1-selectivity of drugs.

Critical Evaluation of Multifunctional Betaxolol Hydrochloride Nanoformulations for Effective Sustained Intraocular Pressure Reduction.

Introduction: Glaucoma is a chronic disease that requires long-term adherence to treatment. Topical application of conventional eye drops results in substantial drug loss due to rapid tear turnover, with poor drug bioavailability being a major challenge for efficient glaucoma treatment. We aimed to prepare the anti-glaucoma drug betaxolol hydrochloride (BH) as a novel nano-delivery system that prolonged the retention time at the ocular surface and improved bioavailability. Methods: We constructed multifunctional nanoparticles (MMt-BH-HA/CS-ED NPs) by ion cross-linking-solvent evaporation method. The particle size, zeta potential, encapsulation efficiency and drug loading of MMt-BH-HA/CS-ED NPs were physicochemically characterized. The structure of the preparations was characterized by microscopic techniques of SEM, TEM, XPS, XRD, FTIR and TGA, and evaluated for their in vitro release performance as well as adhesion properties. Its safety was investigated using irritation assays of hemolysis experiment, Draize test and histopathology examination. Precorneal retention was examined by in vivo fluorescence tracer method and pharmacokinetics in tear fluid was studied. A model of high IOP successfully induced by injection of compound carbomer solution was used to assess the IOP-lowering efficacy of the formulation, and it was proposed that micro-interactions between the formulation and the tear film would be used to analyze the behavior at the ocular surface. Results: The positively charged MMt-BH-HA/CS-ED NPs were successfully prepared with good two-step release properties, higher viscosity, and slower pre-corneal diffusion rate along with longer precorneal retention time compared to BH solution. The micro-interactions between nanoparticles and tear film converted the drug clearance from being controlled by fast aqueous layer turnover to slow mucin layer turnover, resulting in higher drug concentration on the ocular surface, providing more durable and stable IOP-lowering efficacy. Conclusion: The novel multifunctional MMt-BH-HA/CS-ED NPs can effectively reduce IOP and are suitable for the treatment of chronic disease glaucoma.

Design, Synthesis and Evaluation of Novel Molecular Hybrids between Antiglaucoma Drugs and H2S Donors.

Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (H2S) is a gaseous neurotransmitter implicated in various pathophysiological processes. It is involved in the pathological mechanism of glaucomatous neuropathy and exerts promising effects in the treatment of this disease. In this work, we designed and synthetized new molecular hybrids between antiglaucoma drugs and H2S donors to combine the pharmacological effect of both moieties, providing a heightened therapy. Brinzolamide, betaxolol and brimonidine were linked to different H2S donors. The H2S-releasing properties of the new compounds were evaluated in a phosphate buffer solution by the amperometric approach, and evaluated in human primary corneal epithelial cells (HCEs) by spectrofluorometric measurements. Experimental data showed that compounds 1c, 1d and 3d were the hybrids with the best properties, characterized by a significant and long-lasting production of the gasotransmitter both in the aqueous solution (in the presence of L-cysteine) and in the intracellular environment. Because, to date, the donation of H2S by antiglaucoma H2S donor hybrids using non-immortalized corneal cells has never been reported, these results pave the way to further investigation of the potential efficacy of the newly synthesized compounds.

Application of topical betaxolol to cure superficial infantile hemangioma: A pilot study.

BACKGROUND: Beta-blockers have gradually become an attractive option for the treatment of infantile hemangiomas. Topical application is preferred to oral administration because of their potential systemic adverse effects. The aim of this study is to investigate the effect of betaxolol in treating superficial infantile hemangioma. METHODS: Seventy-four infants admitted to the First Affiliated Hospital of Xinjiang Medical University from 2018 to 2019 were observed and recorded. Variables such as color, size, tension, and thickness were recorded monthly and evaluated using visual analog scales. Multi-factor analysis of variance with repeated measurements and the non-parametric Kruskal-Wallis H test were used to compare clinical effectiveness across the different groups. RESULTS: After 6 months of treatment, 33.78% (25/74) showed excellent results, 55.41% (41/74) had good responses, 8.11% (6/74) had moderate responses, and 2.70% (2/74) had poor responses. Local discomfort and systemic complications were not found. There was no significant difference in gender and location of occurrence among groups (p > 0.05), and the effect of topical application of betaxolol was optimum in the children aged 0-3 months (p = 0.002). None of three age groups had statistically significant difference in heart rate and blood pressure after accepting treatment (1 month, p = 0.618; 4 months, p = 0.138; 6 months, p = 0.757). CONCLUSIONS: Our study showed that topical administration of betaxolol was effective and well tolerated for superficial infantile hemangiomas, particularly in the early proliferative stage. However, its safety and efficacy need further research.

ß1- and ß1/ß2-adrenergic receptor antagonists block 6-nitrodopamine-induced contractions of the rat isolated epididymal vas deferens.

6-Nitrodopamine (6-ND) is an endogenous modulator of the contractility in the rat isolated epididymal vas deferens (RIEVD) and considered to be the main peripheral mediator of the emission process. Use of selective and unselective ß-adrenergic receptor antagonists has been associated with ejaculatory failure. Here, the effects of selective ß1- and ß1/ß2-adrenergic receptor antagonists on RIEVD contractions induced by 6-ND, dopamine, noradrenaline, adrenaline, and electric-field stimulation (EFS) were investigated. The selective ß1-adrenergic receptor antagonists atenolol (0.1 and 1 µï»¿M), betaxolol (1 µï»¿M), and metoprolol (1 µï»¿M) and the unselective ß1/ß2-adrenergic receptor antagonists propranolol (1 and 10 µï»¿M) and pindolol (10 µï»¿M) caused significant rightward shifts of the concentration-response curve to 6-ND (pA2 6.41, 6.91, 6.75, 6.47, and 5.74; for atenolol, betaxolol, metoprolol, propranolol, and pindolol), but had no effect on dopamine-, noradrenaline-, and adrenaline-induced contractions. The effects of selective ß1- and ß1/ß2-adrenergic receptor antagonists at a higher concentration (atenolol 1 µï»¿M, betaxolol 1 µï»¿M, metoprolol 1 µï»¿M, propranolol 10 µï»¿M, and pindolol 10 µï»¿M) also reduced the EFS-induced RIEVD contractions in control, but not in RIEVD obtained from L-NAME-treated animals. The selective ß1-adrenoceptor agonist RO-363, the selective ß2-adrenoceptor agonist salbutamol, and the selective ß3-adrenoceptor agonist mirabegron, up to 300 µï»¿M, had no effect on the RIEVD tone. The results demonstrate that ß1- and ß1-/ß2-adrenoceptor receptor antagonists act as 6-ND receptor antagonists in RIEVD, further confirming the main role of 6-ND in the RIEVD contractility.

Topical ophthalmic beta-blockers are associated with ocular pseudopemphigoid: A pharmacovigilance study of antiglaucoma medications utilising the FDA adverse event reporting system.

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.

Chiral separation of ß-blockers by supercritical fluid chromatography using Chiralpak-IG and Chiralpak IBN-5 columns.

Chiral separation of ß-blockers is performed by utilizing the supercritical fluid chromatographic method. The chiral columns utilized were Chiralpak IG and Chiralpak IBN-5. The finest mobile phase was CO2 -0.2% TEA in methanol (60:40). The values atenolol enantiomers retention factors were 6.39 and 8.98. These values for propranolol enantiomers were 3.39 and 4.06. These values for betaxolol enantiomers were 4.08 and 4.68. The separation and resolution factor values for atenolol, propranolol, and betaxolol were 1.41 and 3.33, 1.19 and 2.23, and 1.15 and 1.87, separately and respectively. By comparison, it was observed that Chiralpak IG column is better than Chiralpak IBN-5 column. Supercritical fluid chromatography has been found as the best analytical technique due to its high speed, being eco-friendly, and being economic. The various most probable interactions responsible for the chiral resolution are hydrogen bonding, dipole-dipole interactions, steric effect, and π-π interactions. The reported methods are effective, efficient, and reproducible and may be used to separate and identify atenolol, propranolol, and betaxolol in any unknown samples.

The prophylactic effect of betaxolol 0.5% versus brimonidine 0.2% on IOP elevation after Nd:YAG laser posterior capsulotomy.

CLINICAL RELEVANCE: Posterior capsule opacification is a common late complication of cataract surgery. Posterior capsule opening with Nd:YAG laser, which is the standard treatment, may cause transient elevation of intraocular pressure (IOP). BACKGROUND: To evaluate the efficacy of betaxolol 0.|5% compared to brimonidine 0.2%, in prevention of intraocular pressure increase after Nd:YAG Laser posterior capsulotomy. METHODS: In a double masked randomised clinical trial, 38 eyes from 38 pseudophakic patients over 21 years of age who had significant posterior capsule opacification after phacoemulsification were randomly assigned to receive either betaxolol 0.|5% (18 eyes) or brimonidine 0.|2% (20 eyes) one hour before Nd:YAG Laser posterior capsulotomy.| Exclusion criteria were: glaucoma or history of glaucoma surgery, active uveitis, active ocular infection, pregnancy, unstable cardiovascular condition and severe asthma and lung diseases. Intraocular pressure was measured by Goldmann applanation tonometry, 1 hour before applying the laser and 4 hours after the laser application. RESULTS: There was no statistically significant difference between the two groups regarding the baseline mean IOP and the 4-hour post-laser mean IOP. There was a statistically significant decrease in the 4-hour post-laser mean IOP as compared to the baseline mean IOP in each group. The mean IOP change in the betaxolol group, was -2.39 ± 1.79 mm Hg and in the brimonidine group was -4.25 ± 2.20 mm Hg. The difference was statistically significant (P = 0.007). None of the patients experienced clinically significant IOP increase (≥5 mm Hg) in either group. CONCLUSION: Use of a single topical dose of betaxolol 0.5% and brimonidine 0.2%, 1 hour before laser treatment, can prevent significant acute IOP increase after Nd:YAG laser posterior capsulotomy, and betaxolol may provide a new alternative for prophylactic use.

Short-term efficacy of latanoprostene bunod for the treatment of open-angle glaucoma and ocular hypertension: a systematic literature review and a network meta-analysis.

BACKGROUND/AIMS: To assess the comparative efficacy of latanoprostene bunod (LBN), a novel prostaglandin analogue (PGA), to other medications for open-angle glaucoma and ocular hypertension on lowering intraocular pressure (IOP). METHODS: A systematic literature review adapted from the Li et al (Ophthalmology, 2016) study was conducted. Medline, Embase and PubMed were searched for randomised controlled trials published between 1 January 2014 and 19 March 2020. Studies had to report IOP reduction after 3 months for at least two different treatments among placebo, PGAs (bimatoprost 0.01%, bimatoprost 0.03%, latanoprost, LBN, tafluprost, unoprostone) or apraclonidine, betaxolol, brimonidine, brinzolamide, carteolol, dorzolamide, levobunolol, timolol, travoprost. A Bayesian network meta-analysis was performed to provide the relative effect in terms of mean difference (95% credible interval) of IOP reduction and ranking probabilities. Surface under the cumulative ranking curve (SUCRA) was generated. RESULTS: A total of 106 trials were included with data for 18 523 participants. LBN was significantly more effective than unoprostone (-3.45 (-4.77 to -2.12)). Although relative effect was not significative, compared with other PGAs, LBN numerically outperformed latanoprost (-0.70 (-1.83 to 0.43)) and tafluoprost (-0.41 (-1.87 to 1.07)), was similar to bimatoprost 0.01% (-0.02(-1.59 to 1.55)) and was slightly disadvantaged by bimatoprost 0.03% (-0.17 (-1.42 to 1.07)). LBN was significantly more efficient than the beta-blockers apraclonidine, betaxolol, brimonidine, brinzolamide, carteolol, dorzolamide and timolol. According to SUCRA, LBN was ranked second after bimatoprost 0.03%, followed by bimatoprost 0.01%. CONCLUSION: LBN was significantly more effective than the PGA unoprostone and most of the beta-blockers. Compared with the most widely used PGAs, LBN numerically outperformed latanoprost and travoprost and was similar to bimatoprost 0.01%.

Formulation and evaluation of sustained release ocular inserts of betaxolol hydrochloride using arabinoxylan from Plantago ovata.

The purpose of the current studies was to develop ocular insert of betaxolol hydrochloride (BXH), using arabinoxylan (AX) as a film former. The inserts were prepared by sandwiching I mg of BXH between two films of AX. Six different formulations of ocular inserts were prepared in such a way that first three formulations contained varying concentrations of AX along with glycerol as plasticizer, whereas, rest of the formulations were added with 0.5mg of sodium alginate, sandwiched between two films of AX along with 1mg of BXH. Chemical compatibilities of the ingredients were assessed by using FTIR. Prepared ocular inserts were subjected to various physicochemical characterizations. The dissolution studies showed that ocular inserts containing sodium alginate with the AX showed sustained release effect better than the formulations with AX alone. Addition of sodium alginate resulted in inhibition of sudden release in initial phase and further sustained the release of drug from ocular inserts. Ocular inserts were pH compatible to the eyes as well as there was no interaction among the drug and excipients, suggesting that the selected excipients were suitable for the development of sustained release ocular inserts of BXH.

Wettability and contact angle affect precorneal retention and pharmacodynamic behavior of microspheres.

In the present study, we describe the development of betaxolol hydrochloride and montmorillonite with ion exchange in a single formulation to create a novel micro-interactive dual-functioning sustained-release delivery system (MIDFDS) for the treatment of glaucoma. Betaxolol hydrochloride molecule was loaded onto the montmorillonite by ion exchange and MIDFDS formation was confirmed by XPS data. MIDFDS showed similar physicochemical properties to those of Betoptic, such as particle size, pH, osmotic pressure, and rheological properties. Nevertheless, the microdialysis and intraocular pressure test revealed better in vivo performance of MIDFDS, such as pharmacokinetics and pharmacodynamics. With regards to wettability, MIDFDS had a larger contact angle (54.66 ± 5.35°) than Betoptic (36.68 ± 1.77°), enabling the MIDFDS (2.93 s) to spread slower on the cornea than Betoptic (2.50 s). Moderate spreading behavior and oppositely charged electrostatic micro-interactions had a comprehensive influence on micro-interactions with the tear film residue, resulting in a longer precorneal retention time. Furthermore, MIDFDS had a significant sustained-release effect, with complete release near the cornea. The dual-functioning sustained-release carrier together with prolonged pre-corneal retention time (80 min) provided sufficiently high drug concentrations in the aqueous humor to achieve a more stable and long-term IOP reduction for 10 h. In addition, cytotoxicity and hemolysis tests showed that MIDFDS had better biocompatibility than Betoptic. The dual-functioning microspheres presented in this study provide the possibility for improved compliance due to low cytotoxicity and hemolysis, which suggests promising clinical implications.

Ocular pharmacokinetics of atenolol, timolol and betaxolol cocktail: Tissue exposures in the rabbit eye.

Quantitative understanding of pharmacokinetics of topically applied ocular drugs requires more research to further understanding and to eventually allow predictive in silico models to be developed. To this end, a topical cocktail of betaxolol, timolol and atenolol was instilled on albino rabbit eyes. Tear fluid, corneal epithelium, corneal stroma with endothelium, bulbar conjunctiva, anterior sclera, iris-ciliary body, lens and vitreous samples were collected and analysed using LC-MS/MS. Iris-ciliary body was also analysed after intracameral cocktail injection. Non-compartmental analysis was utilized to estimate the pharmacokinetics parameters. The most lipophilic drug, betaxolol, presented the highest exposure in all tissues except for tear fluid after topical administration, followed by timolol and atenolol. For all drugs, iris-ciliary body concentrations were higher than that of the aqueous humor. After topical instillation the most hydrophilic drug, atenolol, had 3.7 times higher AUCiris-ciliary body than AUCaqueous humor, whereas the difference was 1.4 and 1.6 times for timolol and betaxolol, respectively. This suggests that the non-corneal route (conjunctival-scleral) was dominating the absorption of atenolol, while the corneal route was more important for timolol and betaxolol. The presented data increase understanding of ocular pharmacokinetics of a cocktail of drugs and provide data that can be used for quantitative modeling and simulation.

Betaxolol-loaded niosomes integrated within pH-sensitive in situ forming gel for management of glaucoma.

Blindness and impaired vision are considered as the most troublesome health conditions leading to significant socioeconomic strains. The current study focuses on development of nanoparticulate systems (i.e., niosomes) as drug vehicles to enhance the ocular availability of betaxolol hydrochloride for management of glaucoma. Betaxolol-loaded niosomes were further laden into pH-responsive in situ forming gels to further extend precorneal retention of the drug. The niosomes were evaluated in terms of vesicle size, morphology, size distribution, surface charge and encapsulation efficiency. The optimized niosomes, comprised of Span® 40 and cholesterol at a molar ratio of 4:1, displayed particle size of 332 ± 7 nm, zeta potential of -46 ± 1 mV, and encapsulation efficiency of 69 ± 5%. The optimal nanodispersion was then incorporated into a pH-triggered in situ forming gel comprised of Carbopol® 934P and hydroxyethyl cellulose. The formed gels were translucent, pseudoplastic, mucoadhesive, and displayed a sustained in vitro drug release pattern. Upon instillation of the betaxolol-loaded niosomal gel into rabbits' eyes, a prolonged intraocular pressure reduction and significant enhancement in the relative bioavailability of betaxolol (280 and 254.7%) in normal and glaucomatous rabbits, were attained compared to the marketed eye drops, respectively. Hence, the developed pH-triggered nanoparticulate gelling system might provide a promising carrier for ophthalmic drug delivery and for improved augmentation of glaucoma.

Betaxolol: A comprehensive profile.

Betaxolol is a relatively cardioselective ß-adrenoceptor blocking drug, with no partial agonist (intrinsic sympathomimetic) activity and weak membrane-stabilizing (local anesthetic) activity. Betaxolol selectively and competitively binds to and blocks beta-1 (ß1) adrenergic receptors in the heart, thereby decreasing cardiac contractility and rate. This leads to a reduction in cardiac output and lowers blood pressure. When applied topically in the eye, this agent reduces aqueous humor secretion and lowers the intraocular pressure (IOP). In addition, betaxolol prevents the release of renin, a hormone secreted by the kidneys that causes constriction of blood vessels. Betaxolol (S)-(-)-enantiomer shows higher pharmacological activity. This chapter provides a complete review of nomenclature, physiochemical properties, methods of preparation, identification techniques and various qualitative and quantitative analytical techniques as well as pharmacology of betaxolol. In addition, the chapter also includes review of several methods for enantiomeric separation betaxolol using chromatographic techniques.

Using betaxolol for the prevention of paronychia induced by epidermal growth factor receptor inhibitors: a case-control cohort study.

BACKGROUND: High rates of posttreatment discomfort, infection, recurrence, and increased time to return to work have been noted after nail plate avulsion resulting from epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)-induced paronychia, which may even interrupt the course of treatment for EGFR-TKI therapy. Thus, we conducted this study to determine how effectively a topical ß-blocker, betaxolol, prevents EGFR-TKI-induced paronychia. METHODS: This case-control cohort study included a total of 131 non-small-cell lung cancer patients. The prevention group comprised 40 patients treated with topical betaxolol 0.25% solution to prevent paronychia while they received EGFR-TKI therapy. The control group comprised 91 patients who did not preventively use topical betaxolol 0.25% solution while receiving EGFR-TKI therapy. The patients' age, gender, antineoplastic regimen, duration of antineoplastic treatment before the appearance of lesions, number of involved digits (fingernails or toenails) with lesions, grading of paronychia, and pain score were recorded. RESULTS: In terms of the cumulative incidence of paronychia, significant differences (P < 0.01) were noted at both the 2nd and 3rd months after starting EGFR-TKIs. Furthermore, the average visual analogue scale scores were 3.125 and 6.29 in the prevention group and control group, respectively (P < 0.01). The average grades of paronychia were 1.5 and 2.12 in the prevention group and control group, respectively (P < 0.01). The average numbers of involved digits were 2.25 (range: 1-5 digits) in the prevention group and 3.03 (range: 1-7) in the control group (P = 0.07). CONCLUSIONS: Preventively using topical betaxolol can significantly decrease the incidence, VAS score, and grading of EGFR-TKI-induced paronychia.