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Molecular Pharmaceutics Feb 2020The mechanisms of drug clearance from the aqueous humor are poorly defined. In this study, a cocktail approach was used to simultaneously determine the pharmacokinetics...
The mechanisms of drug clearance from the aqueous humor are poorly defined. In this study, a cocktail approach was used to simultaneously determine the pharmacokinetics of three β-blocker agents after intracameral (ic) injection into the rabbit eyes. Aqueous humor samples were collected and analyzed using LC-MS/MS to determine drug concentrations. Pharmacokinetic parameters were obtained using a compartmental fitting approach, and the estimated clearance, volume of distribution, and half-life values were the following: atenolol (6.44 μL/min, 687 μL, and 73.87 min), timolol (19.30 μL/min, 937 μL, and 33.64 min), and betaxolol (32.20 μL/min, 1421 μL, and 30.58 min). Increased compound lipophilicity (atenolol < timolol < betaxolol) resulted in higher clearance and volume of distributions in the aqueous humor. Clearance of timolol and betaxolol is about 10 times higher than the aqueous humor outflow, demonstrating the importance of other elimination routes (e.g., uptake to iris and ciliary body and subsequent elimination via blood flow).
Topics: Adrenergic beta-1 Receptor Antagonists; Animals; Aqueous Humor; Atenolol; Betaxolol; Chromatography, Liquid; Drug Combinations; Half-Life; Injections, Intraocular; Intraocular Pressure; Male; Metabolic Clearance Rate; Rabbits; Tandem Mass Spectrometry; Timolol; Tissue Distribution
PubMed: 31794668
DOI: 10.1021/acs.molpharmaceut.9b01024 -
Cardiology Journal 2020Early detection and management of elevated blood pressure is crucial in reducing the burden of cardiovascular disease (CVD). The importance of an absolute risk... (Review)
Review
Early detection and management of elevated blood pressure is crucial in reducing the burden of cardiovascular disease (CVD). The importance of an absolute risk assessment and patient risk stratification has been highlighted in the European hypertension guidelines since 2003. Amongst numerous risk factors influencing patient prognosis, elevated heart rate (HR) has been indicated as important predictor of future risk of hypertension, coronary heart disease, sudden cardiac death, heart failure, CVD, stroke, total cancer and mortality. Given that resting HR can be easily determined in clinical practice and modified by lifestyle changes as well as beta-blocker therapy, it seems reasonable that lowering resting HR should be a potential target to reduce disease burden and premature mortality. However, there is a lack of outcome studies of HR lowering in tachycardia-related hypertension. This review outlines the underlying mechanisms of early course hypertension pathophysiology with the critical role of the sympathetic nervous system activation, the prognostic significance of fast HR and the mechanistic rationale for the use of non-pharmacological approaches and/or highly long-acting cardioselective beta-blockers with some consideration given to betaxolol properties.
Topics: Cardiovascular Diseases; Heart Disease Risk Factors; Humans; Hypertension; Risk Factors; Tachycardia
PubMed: 30799548
DOI: 10.5603/CJ.a2019.0021 -
The Cochrane Database of Systematic... Mar 2016Beta blockers are commonly used to treat hypertension. The blood pressure reading is the primary tool for physicians and patients to assess the efficacy of the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Beta blockers are commonly used to treat hypertension. The blood pressure reading is the primary tool for physicians and patients to assess the efficacy of the treatment. The blood pressure lowering effect of beta-1 selective blockers is not known.
OBJECTIVES
To quantify the dose-related effects of various doses and types of beta-1 selective adrenergic receptor blockers on systolic and diastolic blood pressure versus placebo in people with primary hypertension.
SEARCH METHODS
We searched the Database of Abstracts of Reviews of Effectiveness (DARE) for related reviews.We searched the following databases for primary studies: the Cochrane Hypertension Specialised Register (All years to 15 October 2015), CENTRAL via the Cochrane Register of Studies Online (2015, Issue 10), Ovid MEDLINE (1946 to 15 October 2015), Ovid EMBASE (1974 to 15 October 2015) and ClinicalTrials.gov (all years to 15 October 2015).The Hypertension Group Specialised Register includes controlled trials from searches of CAB Abstracts, CINAHL, Cochrane Central Register of Controlled Trials, EMBASE, Food Science and Technology Abstracts (FSTA), Global Health, LILACS, MEDLINE, ProQuest Dissertations & Theses, PsycINFO, Web of Science and the WHO International Clinical Trials Registry Platform (ICTRP).Electronic databases were searched using a strategy combining the Cochrane Highly Sensitive Search Strategy for identifying randomized trials in MEDLINE: sensitivity-maximizing version (2008 revision) with selected MeSH terms and free text terms. No language restrictions were used. The MEDLINE search strategy was translated into CENTRAL, EMBASE, the Hypertension Group Specialised Register and ClinicalTrials.gov using the appropriate controlled vocabulary as applicable. Full strategies are in Appendix 1.
SELECTION CRITERIA
Randomised, double-blind, placebo-controlled parallel or cross-over trials. Studies had to contain a beta blocker monotherapy arm with fixed dose. People enrolled into the studies had to have primary hypertension at baseline. Duration of studies had to be between 3 weeks to 12 weeks. Drugs in this class of beta blockers are atenolol, betaxolol, bevantolol, bisoprolol, esmolol, metoprolol, nebivolol, pafenolol, practolol.
DATA COLLECTION AND ANALYSIS
Two authors confirmed the inclusion of studies and extracted the data independently. Review Manager (RevMan) 5.3.5 was used to synthesise data.
MAIN RESULTS
We identified 56 RCTs (randomised controlled trials) that examined the blood pressure (BP) lowering efficacy of beta-1 selective blockers (beta-1 blocker) in 7812 primary hypertensive patients. Among the included trials, 26 RCTs were parallel studies and 30 RCTs were cross-over studies, examining eight beta-1 blockers. Overall, the majority of beta-1 blockers studied significantly lowered systolic blood pressure (SBP) and diastolic blood pressure (DBP). In people with mild to moderate hypertension, beta-1 selective blockers lowered BP by an average of -10/-8 mmHg and reduced heart rate by 11 beats per minute. The maximum BP reduction of beta-1 blockers occurred at twice the starting dose. Individual beta-1 blockers did not exhibit a graded dose-response effect on SBP and DBP over the recommended dose range.Most beta-1 blockers tested significantly lowered heart rate. A graded dose-response of beta-1 blockers on heart rate was evident. Higher dose beta-1 blockers lowered heart rate more than lower doses. Individually and overall beta-1 blockers did not affect pulse pressure, which distinguishes them from other classes of drugs.
AUTHORS' CONCLUSIONS
This review provides low quality evidence that in people with mild to moderate hypertension, beta-1 selective blockers lowered BP by an average of -10/-8 mmHg and reduced heart rate by 11 beats per minute as compared to placebo. The effect of beta-1 blockers at peak hours, -12/-9 mmHg, was greater than the reduction at trough hours, -8/-7 mmHg. Beta-1 selective blockers lowered BP by a greater magnitude than dual receptor beta-blockers and partial agonist beta-blockers, lowered BP similarly to nonselective beta-blockers. Beta-1 selective blockers lowered SBP by a similar degree and lowered DBP by a greater degree than diuretics, angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Because DBP is lowered by a similar extent to SBP, beta-1 selective blockers do not reduce pulse pressure.
Topics: Adrenergic beta-Antagonists; Antihypertensive Agents; Blood Pressure; Diastole; Essential Hypertension; Heart Rate; Humans; Hypertension; Randomized Controlled Trials as Topic; Systole
PubMed: 26961574
DOI: 10.1002/14651858.CD007451.pub2 -
Experimental Eye Research Nov 2021Our study aims to determine whether the beta-adrenergic system is involved in the regulation of lymphatic drainage from the eye. For this purpose, we assessed the effect...
Our study aims to determine whether the beta-adrenergic system is involved in the regulation of lymphatic drainage from the eye. For this purpose, we assessed the effect of 2 topical beta-adrenergic blockers, timolol and betaxolol, commonly used as glaucoma drugs, on lymphatic clearance of albumin from the aqueous humor to neck lymph nodes. Adult mice were treated with either topical timolol, a non-selective β-blocker, 0.5% (n = 8), or topical betaxolol, a selective β-adrenergic blocker, 0.5% (n = 6) twice daily for 14 days and compared to respective control groups (n = 5 and n = 7). Changes in lymphatic clearance from the eye were assessed using a quantitative in vivo photoacoustic imaging approach. In all subjects, right eye and neck lymph nodes were longitudinally assessed by sequential photoacoustic imaging just prior to near-infrared dye injection into the anterior chamber of the eye, and 20 min, 2 and 4 h after injection. Repeat measurements of mean pixel intensities (MPIs) of right eyes and nodes were performed at all timepoints. The areas under the curves (AUC) were calculated and the AUC of the treated-group was compared to that of controls using the Mann-Whitney U test. The slopes of MPI of each region of interest over time were compared using the linear mixed model after adjusting for IOP decrease after treatment and other parameters such as sex and body weight. In the timolol-treated group, right neck nodes showed significant decrease in AUC signal intensity compared with controls (P = 0.003), and significant decrease in slope of MPI compared with controls (P = 0.0025). In the betaxolol-treated group, right neck nodes showed significant decrease in AUC signal intensity compared with controls (P = 0.02), and significant decrease in slope of MPI compared with controls (P = 0.0069). Topical treatment with timolol and betaxolol reduced lymphatic clearance of albumin from the aqueous humor to the neck lymph nodes. This finding may be relevant for the management of secondary glaucomas and inflammatory eye disease in which the clearance of accumulated proteins and antigen from the eye is important to disease recovery and sight protection. This study suggests that the beta-adrenergic system plays a role in the regulation of lymphatic clearance from the eye.
Topics: Administration, Topical; Adrenergic beta-Antagonists; Animals; Aqueous Humor; Disease Models, Animal; Female; Glaucoma; Intraocular Pressure; Lymphatic Vessels; Male; Mice; Photoacoustic Techniques; Timolol
PubMed: 34599970
DOI: 10.1016/j.exer.2021.108775 -
European Journal of Pharmaceutical... Dec 2020Ocular bioavailability after eye drops administration is an important, but rarely determined, pharmacokinetic parameter. In this study, we measured the pharmacokinetics...
Ocular bioavailability after eye drops administration is an important, but rarely determined, pharmacokinetic parameter. In this study, we measured the pharmacokinetics of a cocktail of three beta blockers after their topical administration into the albino rabbit eye. Samples from aqueous humour were analysed with LC-MS/MS. The pharmacokinetic parameters were estimated using compartmental and non-compartmental analyses. The ocular bioavailability was covering broad range of values: atenolol (0.07 %), timolol (1.22%, 1.51%) and betaxolol (3.82%, 4.31%). Absolute ocular bioavailability presented a positive trend with lipophilicity and the values showed approximately 60-fold range. The generated data enhances our understanding for ocular pharmacokinetics of drugs and may be utilized in pharmacokinetic model building in ophthalmic drug development.
Topics: Administration, Topical; Adrenergic beta-Antagonists; Animals; Atenolol; Betaxolol; Biological Availability; Chromatography, Liquid; Ophthalmic Solutions; Rabbits; Tandem Mass Spectrometry; Timolol
PubMed: 32946960
DOI: 10.1016/j.ejps.2020.105553 -
American Journal of Ophthalmology Aug 2023To compare long-term visual outcomes in the 2 arms of the Early Manifest Glaucoma Trial (EMGT) and determine if delayed treatment was associated with a penalty in terms... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To compare long-term visual outcomes in the 2 arms of the Early Manifest Glaucoma Trial (EMGT) and determine if delayed treatment was associated with a penalty in terms of visual function.
DESIGN
Long-term follow-up of a prospective, randomized controlled clinical trial.
METHODS
EMGT was carried out at 2 centers in Sweden; 255 subjects with newly detected, untreated glaucoma were randomized to immediate treatment with topical betaxolol and argon laser trabeculoplasty or to no initial treatment as long as no progression was detected. Subjects were followed prospectively with standard automated perimetry, visual acuity measurements, and tonometry for up to 21 years. Outcomes included vision impairment (VI), the perimetric mean deviation (MD) index and rate of progression, and visual acuity.
RESULTS
At study end, percentages of eyes with VI or blindness were slightly higher in the treated group than in the untreated control group, 12.1% vs 11.0%, and 9.4.% vs 6.1% respectively, as were subjects with VI in at least one eye, 19.5% vs 18.7%. The differences were not statistically significant, nor were cumulative incidences of VI in at least one eye. The control group had more field loss than the treatment group, with median MD in the worse eye of -14.73 dB vs -12.85 dB, and rate of progression of -0.74 vs -0.60 dB/y, which was not statistically significant. Differences in visual acuity were minimal.
CONCLUSIONS
Delaying treatment did not result in serious penalties. VI occurred at similar proportions in both treatment arms with a slight preponderance in the treatment group, whereas visual field damage was slightly higher in the control group.
Topics: Humans; Glaucoma, Open-Angle; Intraocular Pressure; Prospective Studies; Time-to-Treatment; Glaucoma; Visual Field Tests; Disease Progression; Follow-Up Studies; Vision Disorders
PubMed: 37142174
DOI: 10.1016/j.ajo.2023.04.010 -
Drug Delivery Dec 2023Recently, various novel drug delivery systems have been developed to overcome ocular barriers in order to improve drug efficacy. We have previously reported that...
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.
Topics: Drug Delivery Systems; Eye; Betaxolol; Bentonite; Drug Liberation
PubMed: 36866574
DOI: 10.1080/10717544.2023.2184312 -
International Journal of Molecular... Nov 2022Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (HS) is a gaseous...
Glaucoma is a group of eye diseases consisting of optic nerve damage with corresponding loss of field vision and blindness. Hydrogen sulfide (HS) 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 HS donors to combine the pharmacological effect of both moieties, providing a heightened therapy. Brinzolamide, betaxolol and brimonidine were linked to different HS donors. The HS-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 , and 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 HS by antiglaucoma HS 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.
Topics: Humans; Antiglaucoma Agents; Betaxolol; Gasotransmitters; Glaucoma; Hydrogen Sulfide
PubMed: 36430281
DOI: 10.3390/ijms232213804 -
British Journal of Clinical Pharmacology Nov 19901. The potential interaction between selective beta 1-adrenoceptor blockers and sulphonylureas or biguanides was studied by comparing the beta 1-adrenoceptor antagonist... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
1. The potential interaction between selective beta 1-adrenoceptor blockers and sulphonylureas or biguanides was studied by comparing the beta 1-adrenoceptor antagonist betaxolol with placebo in 12 normal subjects taking glibenclamide or metformin in a single-blind crossover group study. 2. After a 4 day run-in period on no treatment, six subjects took glibenclamide 2.5 mg twice daily, and six subjects took metformin 850 mg twice daily from day 5 to day 19. All subjects took betaxolol 20 mg daily from day 10 to day 13, and placebo from day 5 to day 10 and from day 13 to day 19. 3. Plasma glucose and insulin concentrations were measured fasting and 60 min after a standard breakfast for 3 successive days during each study treatment; plasma potassium, sodium and betaxolol concentrations were also measured. 4. Fasting glucose, insulin and potassium concentrations did not differ significantly between betaxolol and placebo treatment periods in either glibenclamide- or metformin-treated groups. Post-prandial glucose and insulin concentrations were lower and higher, respectively, relative to fasting concentrations but there was no significant difference between any of the treatment periods. Glibenclamide produced significant increases in insulin concentrations compared with drug-free periods (P less than 0.01). Plasma potassium and sodium concentrations were not affected by any of the treatments. 5. Plasma betaxolol concentrations were adequate for beta 1-adrenoceptor blockade. 6. This study suggests that selective beta 1-adrenoceptor blockade with betaxolol does not change fasting or post-prandial glucose-insulin relationships during simultaneous treatment with either the sulphonylurea glibenclamide or the biguanide metformin.
Topics: Adult; Betaxolol; Blood Glucose; Drug Interactions; Fasting; Female; Glyburide; Humans; Insulin; Male; Potassium; Single-Blind Method
PubMed: 2125460
DOI: 10.1111/j.1365-2125.1990.tb03838.x -
Drug Delivery Dec 2021In the present study, we describe the development of betaxolol hydrochloride and montmorillonite with ion exchange in a single formulation to create a novel...
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 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.
Topics: Animals; Bentonite; Betaxolol; Cell Survival; Chemistry, Pharmaceutical; Delayed-Action Preparations; Drug Carriers; Drug Liberation; Female; Hemolysis; Hydrogen-Ion Concentration; Intraocular Pressure; Male; Microspheres; Particle Size; Rabbits; Rheology; Wettability
PubMed: 34569888
DOI: 10.1080/10717544.2021.1981493