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.

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.

Beta-Blockers for Pyogenic Granuloma: A Systematic Review of Case Reports, Case Series, and Clinical Trials

Pyogenic granuloma (PG) is an acquired vascular growth on the skin and mucous membranes. Even though PG is a benign tumor, treatment is required due to associated risk of ulceration and bleeding, cosmetic concerns, and the low likelihood of spontaneous regression. Treatment entails excisional surgery, cryotherapy, or electrocautery; recurrence however is a major problem. Beta-blockers became an attractive option for the treatment of vascular growths after it got approved for infantile hemangioma. PG was found to express beta adrenergic receptors, similarly to infantile hemangioma. Several publications have reported the use of oral and topical beta blockers such as timolol, propranolol, and betaxolol for the treatment of PG. In this study, we summarized the literature with regards to the effectiveness of topical beta blockers for the treatment of PG, and discussed all published case reports, case series, and open-label single arm trials. J Drugs Dermatol. 2019;18(10):1006-1010.

Age-dependent sympathetic neural responses to ß1 selective beta-blockade in untreated hypertension-related tachycardia.

BACKGROUND: Elevated heart rate (HR) increases cardiovascular morbidity and mortality in hypertension. The impact of beta-blockers on patient prognosis in hypertension is controversial. This study examined the age-related effects of betaxolol on HR, muscle sympathetic nerve activity (MSNA), blood pressure (BP) and sympathovagal balance in untreated males with hypertension and tachycardia. METHODS: Ten young (age 26 ± 1 years) and seven older (age 50 ± 4 years) males underwent measurement of BP, HR, HR variability (Poincare plot) and MSNA before and after 8 weeks treatment with betaxolol at the initial starting dose of 10 mg/day, which was increased to 20 mg/day once daily after 4 weeks in all subjects. RESULTS: In younger subjects, betaxolol decreased systolic BP (-13 ± 4 mm Hg, p = .01) and HR (-29 ± 4 bpm, p < .001) but not MSNA (3 ± 3 burst/min., p = 0.47) after 8 weeks. In older subjects a pronounced reduction in BP (-27 ± 7, p = .007) was accompanied by a significant decrease in MSNA (-13 ± 5 burst/min., p < .05) and HR (-17 ± 4 bpm, p = .002). SD1/SD2 ratio of Poincare plot increased in younger (0.36 ± 0.03 vs 0.51 ± 0.05, p = .004), but not in older (0.43 ± 0.08 vs 0.54 ± 0.12, p = .50) subjects. CONCLUSION: Autonomic neural responses to betaxolol are age-dependent in hypertension-related tachycardia. Betaxolol reduces sympathetic drive to the heart, but not to the peripheral vessels confirming the contribution of augmented cardiac sympathetic activity to disease pathophysiology in younger adults. In older hypertensives, the sympathovagal balance is not influenced by betaxolol. The paradoxical reduction in MSNA despite lowering of BP and HR in older patients may suggest age-related functional decrements in autonomic control and/or inhibitory effects of betaxolol on the central nervous system.

Structural and Functional Progression in the Early Manifest Glaucoma Trial.

PURPOSE: To elucidate the temporal relationship between detection of glaucomatous optic disc progression, as assessed by fundus photography, and visual field progression. DESIGN: Prospective, randomized, longitudinal trial. PARTICIPANTS: Three hundred six study eyes with manifest glaucoma with field loss and 192 fellow eyes without any field defect at the start of the trial, from a total of 249 subjects included in the Early Manifest Glaucoma Trial (EMGT), were assessed. METHODS: Evaluation of visual field progression and optic disc progression during an 8-year follow-up period. Three graders independently assessed optic disc progression in optic disc photographs. Visual field progression was assessed using glaucoma change probability maps and the EMGT progression criterion. MAIN OUTCOME MEASURES: Time to detection of visual field progression and optic disc progression. RESULTS: Among study eyes with manifest glaucoma, progression was detected in the visual field first in 163 eyes (52%) and in the optic disc first in 39 eyes (12%); in 1 eye (0%), it was found simultaneously with both methods. Among fellow eyes with normal fields, progression was detected in the visual field first in 28 eyes (15%) and in the optic disc first in 34 eyes (18%); in 1 eye (1%), it occurred simultaneously. CONCLUSIONS: In eyes with manifest glaucoma, progression in the visual field was detected first more than 4 times as often as progression in the optic disc. Among fellow eyes without visual field loss at baseline, progression was detected first as frequently in the optic disc as in the visual field.

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%.

[Beta-adrenoblockers for the correction of arterial hypertension in postmenopausal women].

The use of beta-blockers is an important component of therapy of cardiovascular pathology (e.g. coronary heart disease, arterial hypertension) in menopausal women. Comparative data on the efficiency of lokren and carvedilol for the correction of grade 2 AH are presented.

Identification of therapeutics that target eEF1A2 and upregulate utrophin A translation in dystrophic muscles.

Up-regulation of utrophin in muscles represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy. We previously demonstrated that eEF1A2 associates with the 5'UTR of utrophin A to promote IRES-dependent translation. Here, we examine whether eEF1A2 directly regulates utrophin A expression and identify via an ELISA-based high-throughput screen, FDA-approved drugs that upregulate both eEF1A2 and utrophin A. Our results show that transient overexpression of eEF1A2 in mouse muscles causes an increase in IRES-mediated translation of utrophin A. Through the assessment of our screen, we reveal 7 classes of FDA-approved drugs that increase eEF1A2 and utrophin A protein levels. Treatment of mdx mice with the 2 top leads results in multiple improvements of the dystrophic phenotype. Here, we report that IRES-mediated translation of utrophin A via eEF1A2 is a critical mechanism of regulating utrophin A expression and reveal the potential of repurposed drugs for treating DMD via this pathway.

Meta-analysis of medical intervention for normal tension glaucoma.

OBJECTIVE: To evaluate the intraocular pressure (IOP) reduction achieved by the most frequently prescribed antiglaucoma drugs in patients with normal tension glaucoma (NTG). DESIGN: Systematic review and meta-analysis. PARTICIPANTS: Fifteen randomized clinical trials reported 25 arms for peak IOP reduction, 16 arms for trough IOP reduction, and 13 arms for diurnal curve IOP reduction. METHODS: Pertinent publications were identified through systematic searches of PubMed, EMBASE, and the Cochrane Controlled Trials Register. The patients had to be diagnosed as having NTG. Methodological quality was assessed by the Delphi list on a scale from 0 to 18. The pooled 1-month IOP-lowering effects were calculated using the 2-step DerSimonian and Laird estimate method of the random effects model. MAIN OUTCOME MEASURES: Absolute and relative reductions in IOP from baseline for peak and trough moments. RESULTS: Quality scores of included studies were generally high, with a mean quality score of 12.7 (range, 9-16). Relative IOP reductions were peak, 15% (12%-18%), and trough, 18% (8%-27%) for timolol; peak, 14% (8%-19%), and trough, 12% (-7% to 31%) for dorzolamide; peak, 24% (17%-31%), and trough, 11% (7%-14%) for brimonidine; peak, 20% (17%-24%), and trough, 20% (18%-23%) for latanoprost; peak, 21% (16%-25%), and trough, 18% (14%-22%) for bimatoprost. The differences in absolute IOP reductions between prostaglandin analogues and timolol varied from 0.9 to 1.0 mmHg at peak and -0.1 to 0.2 mmHg at trough. CONCLUSIONS: Latanoprost, bimatoprost, and timolol are the most effective IOP-lowering agents in patients with NTG.

Disc hemorrhages and treatment in the early manifest glaucoma trial.

PURPOSE: To evaluate the effect of intraocular pressure (IOP)-reducing treatment on the development of disc hemorrhages in patients with glaucoma. DESIGN: Prospective cohort study of patients in the Early Manifest Glaucoma Trial, followed up to 11 years (median = 8 years). PARTICIPANTS: Patients with newly detected glaucoma randomized to argon laser trabeculoplasty plus betaxolol (n = 129) or no initial treatment (n = 126), followed with tonometry, perimetry, and ophthalmoscopy every 3 months, and fundus photography every 6 months. METHODS: Logistic regression expressed as odds ratios (OR) and 95% confidence intervals (CIs), analysis of variance, and Cox time-dependent models, expressed as hazard ratios (HRs) and CIs. MAIN OUTCOME MEASURES: Presence (yes/no) and frequency of disc hemorrhages. RESULTS: Disc hemorrhages were identified in approximately 55% of all patients, whether by ophthalmoscopy or review of photographs. In analyses including data up to the time of progression, disc hemorrhages were equally common among treated and control patients: 51.2% versus 45.2%, respectively (P = 0.34), based on ophthalmoscopy, and 50.4% versus 44.4%, respectively (P = 0.34), based on photographs. Gender was the only factor related to the presence of disc hemorrhages detected by both ophthalmoscopy (OR = 0.48; CI, 0.26-0.88; P = 0.022) and photographs (OR = 0.64; CI, 0.38-1.09; P = 0.099) for male patients. The frequency of disc hemorrhages over time did not differ between treated and control patients: 8.4% versus 8.5%, respectively (P = 0.93), based on ophthalmoscopy, and 12.4% versus 11.2%, respectively (P = 0.36), based on photographs. Disc hemorrhages were significantly associated with time to progression (HR = 1.02; CI, 1.01-1.04), and there was no evidence of interaction between treatment group and disc hemorrhages. CONCLUSIONS: IOP-reducing treatment was unrelated to the presence or frequency of disc hemorrhages. The results may suggest that disc hemorrhages cannot be considered an indication of insufficient IOP-lowering treatment, and that glaucoma progression in eyes with disc hemorrhages cannot be totally halted by IOP reduction. The results also suggest that disc hemorrhages do not occur in all patients with glaucoma.

[Genetic aspects of individual sensitivity to betaxolol in patients with arterial hypertension].

Association of polymorphism of b1-adrenoreceptors gene and cytochrome 2D6 gene with efficacy of b-adrenoblocker betaxolol was studied in 81 patients with I and II degree arterial hypertension. Betaxolol (10-20 mg/day) was given for 4 weeks, its efficacy was assessed by office blood pressure (BP) measurements, 24-hour BP and ECG monitoring and standard exercise test. At the end of the study significant lowering of systolic and diastolic BP was noted by 11,8 +/- 2,47 (p=0,001) and 7,8 +/- 1,68 mm Hg (p=0,001), respectively. Heart rate (HR) at rest lowered by 19,8 +/- 1,96 beats/min (p=0,0001). At analysis of individual reaction of patients to treatment with betaxolol it turned out that decrease of BP and HR was variable, but their distribution in the group did not differ significantly from normal. Hypotensive activity and influence on HR were confirmed by results of all instrumental investigations. No significant differences were revealed in dynamics of systolic and diastolic BP both at rest and at effort between patients with different genotypes of polymorphic marker Gly389Arg of ADRB1 gene. Compared with carriers of genotype Ser/Ser carriers of genotype Ser/Pro of polymorphic marker Pro34Ser of Cyp2D6 gene had significantly more pronounced decrease of HR at the background of treatment with betaxolol: - 32,6 +/- 4,77 and - 18,4 +/- 2,01 beats/min (p=0,023) at rest and - 30,1 +/- 3,05 and - 24,0 +/- 2,59 beats/min (p=0,043) at maximal exercise, respectively. These patients had also more pronounced lowering of diastolic BP at maximal work load and more pronounced increase of exercise duration at the background of treatment. Thus efficacy of betaxolol in patients with hypertension was associated solely with genotype of polymorphic marker Ser34Pro of CYP2D6 gene. In patients having in genotype Pro allele of polymorphic marker Pro34Ser of CYP2D6 gene therapy with betaxolol is more effective, than in homozygote carriers of Ser allele. This can be related to low rate of metabolism of the preparation in these patients.

Controlled drug delivery for glaucoma therapy using montmorillonite/Eudragit microspheres as an ion-exchange carrier.

BACKGROUND: Glaucoma is a serious eye disease that can lead to loss of vision. Unfortunately, effective treatments are limited by poor bioavailability of antiglaucoma medicine due to short residence time on the preocular surface. MATERIALS AND METHODS: To solve this, we successfully prepared novel controlled-release ion-exchange microparticles to deliver betaxolol hydrochloride (BH). Montmorillonite/BH complex (Mt-BH) was prepared by acidification-intercalation, and this complex was encapsulated in microspheres (Mt-BH encapsulated microspheres [BMEMs]) by oil-in-oil emulsion-solvent evaporation method. The BH loaded into ion-exchange Mt was 47.45%±0.54%. After the encapsulation of Mt-BH into Eudragit microspheres, the encapsulation efficiency of BH into Eudragit microspheres was 94.35%±1.01% and BH loaded into Eudragit microspheres was 14.31%±0.47%. RESULTS: Both Fourier transform infrared spectra and X-ray diffraction patterns indicated that BH was successfully intercalated into acid-Mt to form Mt-BH and then Mt-BH was encapsulated into Eudragit microspheres to obtain BMEMs. Interestingly, in vitro release duration of the prepared BMEMs was extended to 12 hours, which is longer than both of the BH solution (2.5 hours) and the conventional BH microspheres (5 hours). Moreover, BMEM exhibited lower toxicity than that of BH solution as shown by the results of cytotoxicity tests, chorioallantoic membrane-trypan blue staining, and Draize rabbit eye test. In addition, both in vivo and in vitro preocular retention capacity study of BMEMs showed a prolonged retention time. The pharmacodynamics showed that BMEMs could extend the drug duration of action. CONCLUSION: The developed BMEMs have the potential to be further applied as ocular drug delivery systems for the treatment of glaucoma.

Montmorillonite/chitosan nanoparticles as a novel controlled-release topical ophthalmic delivery system for the treatment of glaucoma.

BACKGROUND: To date, the rapid clearance from ocular surface has been a huge obstacle for using eye drops to treat glaucoma, since it has led to the short preocular residence time and low bioavailability. METHODS: The novel nanoparticles (NPs) were designed for topical ophthalmic controlled drug delivery system through intercalating the BH into the interlayer gallery of Na-montmorillonite (Na+Mt) and then further enchasing chitosan nanoparticles. The resulting nanoparticles had a positive charge (+29±0.18 mV) with an average diameter of 460±0.6 nm. RESULTS: In vitro study of drug release profiles suggested controlled release pattern. The irritation experiment analysis on both human immortalized cornea epithelial cell (iHCEC) and chorioallantoic membrane-trypan blue staining (CAM-TBS) showed good tolerance for ocular tissues. It was interestingly found that the nanoparticles could enter into iHCEC from the result of cellular uptake experiment measured by confocal layer scan microscopy (CLSM). Meanwhile, multilayered iHCEC was used to simulate the barrier of corneal epithelial cells for in vivo preocular retention capacity study, which suggested that BH-Mt/CS NPs could prolong the retention time in comparison with BH solution. The ocular pharmacokinetics studied by microdialysis sampling technique showed that AUC0-t and MRT0-t of BH-Mt/CS NPs were 1.99-fold and 1.75-fold higher than those of BH solution, indicating higher bioavailability. Moreover, the study of blood drug concentration, few researchers have reported, showed that low level drug could enter into blood, suggesting lower systematic side effect. Importantly, pharmacodynamics studies suggested that BH-Mt/CS NPs could make a significant decreased intraocular pressure on glaucomatous rabbits. CONCLUSION: Inspired by these advance of montmorillonite/chitosan nanoparticles, we envision that the BH-Mt/CS NPs will be a potential carrier for BH, opening up the possible applications in glaucoma therapy.

Predictors of long-term progression in the early manifest glaucoma trial.

PURPOSE: To determine progression factors at the end of the Early Manifest Glaucoma Trial (EMGT) based on all EMGT patients and evaluate separately patients with higher and lower baseline intraocular pressure (IOP; median split). DESIGN: Cohort of clinical trial participants. PARTICIPANTS: Patients with early open-angle glaucoma randomized to argon laser trabeculoplasty plus betaxolol (n = 129) or no immediate treatment (n = 126), examined every 3 months for up to 11 years. METHODS: Cox proportional hazard analyses, expressed by hazard ratios (HRs) and 95% confidence intervals (CIs). MAIN OUTCOME MEASURE: Time to progression, defined by perimetric and photographic disc criteria. RESULTS: Overall progression was 67% when follow-up ended (median, 8 years). Treatment approximately halved progression risk (HR, 0.53; 95% CI, 0.39-0.72); results were similar for patients with higher and lower baseline IOP (HRs, 0.41 and 0.55). Baseline progression factors (HRs, 1.51-2.12; P<0.01) were higher IOP, exfoliation, bilateral disease, and older age, as previously reported. New baseline predictors were lower ocular systolic perfusion pressure in all patients (< or =160 mmHg; HR, 1.42; 95% CI, 1.04-1.94), cardiovascular disease history (HR, 2.75; 95% CI, 1.44-5.26) in patients with higher baseline IOP, and lower systolic blood pressure (BP) (< or =125 mmHg; HR, 0.46; 95% CI, 0.21-1.02) in patients with lower baseline IOP. Postbaseline progression factors were IOP levels at follow-up, with 12% to 13% average increase per millimeter of mercury in all patients (HRs, 1.12-1.13 per mmHg higher) and similar results in patients with higher and lower baseline IOP (HRs, 1.15 and 1.13 per mmHg higher). Disc hemorrhages (HR, 1.02; 95% CI, 1.01-1.03 per percent higher frequency) also predicted progression. Thinner central corneal thickness (CCT) (HR, 1.25; 95% CI, 1.01-1.55 per 40 microm lower) was a new significant factor, a result observed in patients with higher baseline IOP (HR, 1.42; 95% CI, 1.05-1.92 per 40 microm lower) but not lower baseline IOP, with significant IOP-CCT interaction. CONCLUSIONS: Treatment and follow-up IOP continued to have a marked influence on progression, regardless of baseline IOP. Other significant factors were age, bilaterality, exfoliation, and disc hemorrhages, as previously determined. Lower systolic perfusion pressure, lower systolic BP, and cardiovascular disease history emerged as new predictors, suggesting a vascular role in glaucoma progression. Another new factor was thinner CCT, with results possibly indicating a preferential CCT effect with higher IOP.

Fluctuation of intraocular pressure and glaucoma progression in the early manifest glaucoma trial.

PURPOSE: To investigate whether increased fluctuation of intraocular pressure (IOP) is an independent factor for glaucoma progression. DESIGN: A cohort of patients was followed up in a randomized clinical trial. PARTICIPANTS: Two hundred fifty-five glaucoma patients from the Early Manifest Glaucoma Trial (EMGT; 129 treated and 126 control patients). METHODS: Study visits, conducted every 3 months, included ophthalmologic examinations, IOP measurements, and standard automated perimetry, with fundus photography every 6 months. Intraocular pressure values were included only until the time of progression in those eyes that showed such progression. Individual mean follow-up IOP and IOP fluctuation, calculated as the standard deviation of IOP at applicable visits, were the variables of main interest. Cox regression with time-dependent variables was used to evaluate the association between IOP fluctuation and time to progression, both with and without IOP mean in the models. These analyses also controlled for other significant variables. MAIN OUTCOME MEASURES: Glaucoma progression, as defined by a predetermined visual field criterion, worsening of the disk, assessed by an independent disc reading center, or both. RESULTS: Median follow-up time was 8 years (range, 0.1-11.1 years). Sixty-eight percent of the patients progressed. When considering mean follow-up IOP and IOP fluctuation in the same time-dependent model, mean IOP was a significant risk factor for progression. The hazard ratio (HR) was 1.11 (95% confidence interval [CI], 1.06-1.17; P<0.0001). Intraocular pressure fluctuation was not related to progression, with an HR of 1.00 (95% CI, 0.81-1.24; P = 0.999). CONCLUSIONS: These results confirm our earlier finding that elevated IOP is a strong factor for glaucoma progression, with the HR increasing by 11% for every 1 mmHg of higher IOP. Intraocular pressure fluctuation was not an independent factor in our analyses, a finding that conflicts with some earlier reports. One explanation for the discrepancy is that our analyses did not include postprogression IOP values, which would be biased toward larger fluctuations because of more intensive treatment. In contrast, in this EMGT report, no changes in patient management occurred during the period analyzed.

Betaxolol, a selective beta(1)-adrenergic receptor antagonist, diminishes anxiety-like behavior during early withdrawal from chronic cocaine administration in rats.

BACKGROUND: Anxiety has been indicated as one of the main symptoms of the cocaine withdrawal syndrome in human addicts and severe anxiety during withdrawal may potentially contribute to relapse. As alterations in noradrenergic transmission in limbic areas underlie withdrawal symptomatology for many drugs of abuse, the present study sought to determine the effect of cocaine withdrawal on beta-adrenergic receptor (beta(1) and beta(2)) expression in the amygdala. METHODS: Male Sprague Dawley rats were administered intraperitoneal (i.p.) injections of cocaine (20 mg/kg) once daily for 14 days. Two days following the last cocaine injection, amygdala brain regions were micro-dissected and processed for Western blot analysis. Results showed that beta(1)-adrenergic receptor, but not beta(2)-adrenergic receptor expression was significantly increased in amygdala extracts of cocaine-withdrawn animals as compared to controls. This finding motivated further studies aimed at determining whether treatment with betaxolol, a highly selective beta(1)-adrenergic receptor antagonist, could ameliorate cocaine withdrawal-induced anxiety. In these studies, betaxolol (5 mg/kg via i.p. injection) was administered at 24 and then 44 h following the final chronic cocaine administration. Anxiety-like behavior was evaluated using the elevated plus maze test approximately 2 h following the last betaxolol injection. Following behavioral testing, betaxolol effects on beta(1)-adrenergic receptor protein expression were examined by Western blotting in amygdala extracts from rats undergoing cocaine withdrawal. RESULTS: Animals treated with betaxolol during cocaine withdrawal exhibited a significant attenuation of anxiety-like behavior characterized by increased time spent in the open arms and increased entries into the open arms compared to animals treated with only saline during cocaine withdrawal. In contrast, betaxolol did not produce anxiolytic-like effects in control animals treated chronically with saline. Furthermore, treatment with betaxolol during early cocaine withdrawal significantly decreased beta(1)-adrenergic receptor protein expression in the amygdala to levels comparable to those of control animals. CONCLUSIONS: The present findings suggest that the anxiolytic-like effect of betaxolol on cocaine-induced anxiety may be related to its effect on amygdalar beta(1)-adrenergic receptors that are up-regulated during early phases of drug withdrawal. These data support the efficacy of betaxolol as a potential effective pharmacotherapy in treating cocaine withdrawal-induced anxiety during early phases of abstinence.

Association of CYP2D6 and ADRB1 genes with hypotensive and antichronotropic action of betaxolol in patients with arterial hypertension.

Betaxolol is a selective antagonist of beta(1)-adrenergic receptors. Personal response to the drug widely varies and depends on its properties and individual features including innate characteristics. Our aim was to study the association between the clinical response to betaxolol in patients with essential hypertension (EH) and polymorphous markers of two genes: beta(1) adrenergic receptor gene (ADRB1) and cytochrome P450 2D6 gene (CYP2D6). Eighty-one patients with EH were selected. Mean age was 52.2 +/- 1.22 years. Betaxolol monotherapy provided effective blood pressure control (BP < 140/90 mmHg) in 68 patients, 56 of them continued treatment with initial dose. The systolic (SBP) and diastolic (DBP) blood pressure declined significantly at the end of the study. We have not found any significant association of rest and exercise BP and heart rate (HR) with polymorphous marker Arg389Gly of ADRB1 gene except the nighttime variability of DBP. But in case of the polymorphous marker Pro34Ser of CYP2D6 gene we have found significant association with response to betaxolol therapy. The rest HR declined more significantly in Ser/Pro genotype carriers (-32.6 +/- 4.77 beats/min and -18.4 +/- 2.01 beats/min, P = 0.023). These patients demonstrated more significant increase of exercise time (4.58 +/- 0.90 and 0.59 +/- 0.58 min, P = 0.045). Maximal exercise HR and DBP were also significantly lower in Ser/Pro genotype carriers in comparison with Ser/Ser genotype carriers. Decline of mean daytime SBP in 24-h ambulatory blood pressure monitoring was more significant in Pro allele carriers (-21.0 +/- 2.55 mmHg vs. -5.2 +/- 2.27 mmHg in patients with Ser/Ser genotype, P = 0.001). Betaxolol effect on HR and BP significantly depends on variability of the gene determining the drug metabolism. The carriers of Pro34 allele of CYP2D6 gene (8.6%) are more sensitive to betaxolol therapy. Because of the relatively small group sizes our data should be considered as preliminary ones. The increase of our groups and the replication in other studies will permit to estimate the contribution of genetic factors to betaxolol effect on HR and BP.

[The smoothness index of betaxolol hydrochloride in patients with newly diagnosed hypertension]. / Smoothness index betaxolol hydrochloridu u pacientu s terstve zjitenou hypertenzí.

INTRODUCTION: 24-hour ambulatory blood pressure monitoring (ABPM) has a higher predictive value for cardiovascular diseases than occasional blood pressure (BP) measurement with sphygmomanometer. ABPM allows for the assessment of 24-hour effect of drugs administered once a day using the smoothness index (SI) method. OBJECTIVE OF WORK: Find out the 24-hour effect of betaxolol hydrochloride administered once a day by determining the smoothness index. Cohort and methodology: Examination of 30 newly diagnosed hypertonics prior to and after 3-month treatment with betaxolol hydrochloride at an average dose of 15 mg once a day. BP measurement using sphygmomanometer and ABPM (SpaceLabs 90207) according to European Society for Hypertension criteria. Determining the smoothness index from individual average hourly changes in BP after treatment by dividing the hourly values average by standard deviation. Calculation of average SI from individual patient data with standard deviation and 95% confidence interval (95% CI). RESULT: The calculated SI value of betaxolol hydrochloride was 1.03 +/- 0.65 (95% CI, 0.80 to 1.26) and 1.27 +/- 0.89 (95% CI, 0.95 to 1.59) for systolic and diastolic BP, respectively. CONCLUSION: Average SI of betaxolol hydrochloride is higher than 1 when both systolic and diastolic BP is measured. Based on the above parameter, the monitored drug has a sufficient 24-hour effect and can be administered once a day.