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.

Design of circular-ring film embedded contact lens for improved compatibility and sustained ocular drug delivery.

Contact lenses are ideal medical devices to sustain the release of ophthalmic drugs. However, the incorporation of drug loaded system can cause visual obstruction and poor oxygen/light permeability which restrict the application of contact lens for long-term wearing. Inspired by the physiological structure of our human eyes, we assume a circular-ring type inner layer embedded CLs might be a good solution to address the above-mentioned problems. In this study, taking betaxolol hydrochloride (BH) as a model drug, its complex with ion exchange resin was used as a carrier for adjusting drug loading amount, which is being dispersed into circular-ring shape Eudragit® S100 film as an inner layer, silicone-based hydrogel as the outer layer. Influence of resin particle size and drug/S100 ratio on drug release profiles was investigated. It was demonstrated that using resin as a carrier can not only increase drug loading amount but also sustain drug release, with the drug release rate well-tuned by either changing particle size of the resin or S100 ratio. Meanwhile S100 can well function as a pH-triggered drug release matrix, with limited drug leakage in the storage medium. Light transmittance of over 97% was achieved in the novel circular-ring layer-embedded CLs. Oxygen permeability coefficient (Dk) of the circular-ring film embedded CLs was 31.1 ± 3.7 barrer, similar to that of pure CLs. The sustained drug release behavior of this circular-ring embedded CLs was also well demonstrated in vivo. A level A IVIVC between in vitro drug release and in vivo drug concentration in tear fluid of the circular-ring embedded CLs was established. In conclusion, this circular-ring embedded contact lens is very promising for ophthalmic drug delivery with enhanced compatibility, sustained and pH triggered drug release characteristics.

Incorporation of ion exchange functionalized-montmorillonite into solid lipid nanoparticles with low irritation enhances drug bioavailability for glaucoma treatment.

Montmorillonite-loaded solid lipid nanoparticles with good biocompatibility, using Betaxolol hydrochloride as model drug, were prepared by the melt-emulsion sonication and low temperature-solidification methods and drug bioavailability was significantly improved in this paper for the first time to application to the eye. The appropriate physical characteristics were showed, such as the mean particle size, Zeta potential, osmotic pressure, pH values, entrapping efficiency (EE%) and drug content (DC%), all showed well suited for possible ocular application. In vitro release experiment indicated that this novel system could continuously release 57.83% drugs within 12 h owing to the dual drug controlled-release effect that was achieved by ion-exchange feature of montmorillonite and structure of solid lipid nanoparticles. Low irritability and good compatibility of nanoparticles were proved by both CAM-TBS test and cytotoxicity experiment. We first discovered from the results of Rose Bengal experiment that the hydrophilicity of the drug-loaded nanoparticles surface was increased during the loading and releasing of the hydrophilic drug, which could contribute to prolong the ocular surface retention time of drug in the biological interface membrane of tear-film/cornea. The results of in vivo pharmacokinetic and pharmacodynamics studies further confirmed that increased hydrophilicity of nanoparticles surface help to improve the bioavailability of the drug and reduce intraocular pressure during administration. The results suggested this novel drug delivery system could be potentially used as an in situ drug controlled-release system for ophthalmic delivery to enhance the bioavailability and efficacy.

Treatment of epidermal growth factor receptor inhibitor-induced severe paronychia with pyogenic granuloma-like lesions with topical betaxolol: an open-label observation study.

BACKGROUND: Paronychia is a common adverse event caused by epidermal growth factor receptor (EGFR) inhibitors. However, high rates of post-treatment discomfort, infection, recurrence, and increased time to return to work have been noted after nail plate avulsion for EGFR inhibitor-induced paronychia. Furthermore, poor wound healing and malnutrition were common conditions found in cancer patients. The aim of this study is to find an effective, pain-relieving, and noninvasive treatment for patients with severe paronychia induced by EGFR inhibitors. METHODS: Data from a series of 35 non-small cell lung cancer cases suffering from EGFR inhibitor-induced paronychia with pyogenic granuloma-like lesions of digits treated with betaxolol 0.25% ophthalmic solution once daily were collected and analyzed. RESULTS: Of the 35 patients suffering from grade 2 or 3 paronychia with pyogenic granuloma-like lesions induced by EGFR inhibitors, 34 (97.1%) demonstrated complete resolution and only one (2.9%) had partial resolution after 12 weeks of topical betaxolol treatment. The grading of paronychia according to the Common Terminology Criteria for Adverse Events decreased from an average of 2.29 to 0.63 after 4 weeks of treatment (P = 5.55 × 10-16 ). All the patients had significant improvement (50% pain reduction), as their pain visual analogue scale scores decreased from an average of 7.06 to 2.26 after one week of treatment (P = 6.11 × 10-25 ). CONCLUSION: Betaxolol 0.25% ophthalmic solution is an effective, safe, and pain-relieving treatment for patients suffering from EGFR inhibitor-induced paronychia with pyogenic granuloma-like lesions and deep fissures.

Ocular Intracameral Pharmacokinetics for a Cocktail of Timolol, Betaxolol, and Atenolol in Rabbits.

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 ß-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).

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.

Sustained ophthalmic delivery of highly soluble drug using pH-triggered inner layer-embedded contact lens.

In the present work the feasibility of using inner layer-embedded contact lenses (CLs) to achieve sustained release of highly water soluble drug, betaxolol hydrochloride (BH) on the ocular surface was investigated. Blend film of cellulose acetate and Eudragit S100 was selected as the inner layer, while silicone hydrogel was used as outer layer to construct inner layer-embedded contact lenses. Influence of polymer ratio in the blend film on in vitro drug release behavior in phosphate buffered solution or simulated tear fluid was studied and drug-polymer interaction, erosion and swelling of the blend film were characterized to better understand drug-release mechanism. Storage stability of the inner layer-embedded contact lenses in phosphate buffer solution was also conducted, with ignorable drug loss and negligible change in drug release pattern within 30 days. In vivo pharmacokinetic study in rabbits showed sustained drug release for over 240 h in tear fluid, indicating prolonged drug precorneal residence time. In conclusion, cellulose acetate/Eudragit S100 inner layer-embedded contact lenses are quite promising as controlled-release carrier of highly water soluble drug for ophthalmic delivery.

A novel ion-exchange carrier based upon liposome-encapsulated montmorillonite for ophthalmic delivery of betaxolol hydrochloride.

As a novel ion-exchange carrier with high surface area and excellent exchangeability, montmorillonite (Mt) was intercalated with betaxolol hydrochloride (BH) to form a nanocomposite and then encapsulated by liposomes (Mt-BH-LPs) for an ophthalmic drug-delivery system. The Mt-BH and Mt-BH-LPs were prepared by an acidification process and ethanol injection combined with ammonium sulfate gradient methods. The successful formation of Mt-BH and Mt-BH-LPs was verified by thermogravimetric analysis, X-ray diffraction, Fourier-transform infrared spectra, and transmission electron microscopy. Mt-BH-LPs possessed the favorable physical characteristics of encapsulation efficiency, drug loading, mean particle size, and ζ-potential. In vitro release studies indicated Mt-BH-LPs effectively maintained a relatively sustained slow release. Immortalized human corneal epithelial cell cytotoxicity, in vivo rabbit eye-irritation tests, and chorioallantoic membrane-trypan blue staining all revealed that Mt-BH-LPs had no obvious irritation on ocular tissues. A new in vitro tear-turnover model, including inserts containing human corneal epithelial cells, was designed to evaluate the precorneal retention time of Mt-BH-LPs. The results showed that Mt-BH-LPs maintained a certain BH concentration in tear fluid for a longer period than the BH solution. In vivo precorneal retention studies also indicated Mt-BH-LPs prolonged drug retention on the ocular surface more than the BH solution. Furthermore, pharmacodynamic studies showed that Mt-BH-LPs had a prolonged effect on decreasing intraocular optical pressure in rabbits. Our results demonstrated that Mt-BH-LPs have potential as an ophthalmic delivery system.

[Preservative-free betaxolol for POAG patients: evaluation of hypotensive effect and ocular surface safety].

AIM: To evaluate ocular surface changes in patients with primary open-angle glaucoma (POAG) as well as the hypotensive effect of preservative-free betaxolol eye drops. MATERIAL AND METHODS: A total of 22 patients (42 eyes) aged 55-83 with POAG stage I-II were examined. All of them were switched from betaxolol b.i.d. to its preservative-free analogue (Xonef BK). The baseline examination included visual acuity measurement, Morisky-Green test (questionnaire), Norn test, Schirmer's test, lissamine green staining, and ocular tonometry. The latter was repeated 2 and 4 weeks after the drug had been switched, while the whole complex--2 months after the beginning of the study. RESULTS: The total tear production in POAG patients under betaxolol therapy was 19.1 ± 10.6 mm. After the 2 months of preservative-free betaxolol use there were no statistically significant changes in Schirmer's test results (p = 0.248). Tear film break-up time (Norn test) improved from 7.8 ± 0.5 secto 9.8 ± 0.8 sec (p = 0.067) as well as the results of lissamine green staining (W = 90.0, p < 0.022). In the Morisky-Green Test betaxolol patients scored only 2.6 ± 0.05 points on average, thus showing non-compliance. After the 2 months of preservative-free betaxolol instillations the scores increased up to 3.1 ± 0.07 (p = 0.04). According to Dunnett's test, used for multiple comparisons, intraocular pressure did not change significantly in either of the study periods (baseline and follow-up measurements at weeks 2, 4, and 8 were taken into account). CONCLUSION: The study proves Xonef BK safe, effective, and appropriate in all types of glaucoma.

[Clonidine poisoning in a child: a case report]. / Intoxication pédiatrique sévère avec une faible dose de clonidine : à propos d'un cas.

Clonidine poisoning's clinical feature is well documented in the medical literature, but the minimal toxic dose has not yet been established. The effectiveness of naloxone is also controversial. The authors describe a clonidine overdose in a 9-year-old boy (25 kg) during a growth hormone test: he received tenfold the prescribed clonidine dose (0.23 mg instead of 0.023 mg) with 6.2 mg betaxolol. About 40 min later, he became drowsy and then complained of low blood pressure, bradycardia, and myosis. By maintaining the Trendelenburg position, administering fluids as well as salbutamol and naloxone (three doses of 0.2 mg were required), he recovered and was discharged from the hospital on day 2. The minimal clonidine toxic dose, the clinical picture, and the effectiveness of naloxone administration are discussed in this paper.

ADRB1 and ADBR2 gene polymorphisms and the ocular hypotensive response to topical betaxolol in healthy Mexican subjects.

BACKGROUND: The ß adrenergic receptors (ADRB) are expressed in the ciliary body and trabecular meshwork, structures involved in aqueous humor production and outflow, respectively. ADRB are members of the adrenergic family of G-protein-coupled receptors. Topic ß blockers have a good local and systemic tolerance; they reduce the aqueous humor production and eye strain blocking the ADRB of the ciliary body and interfering with adenylate cyclase. However, the ocular hypotensive response is not the same in all patients and could be mediated by the polymorphisms of the ADRB genes. MATERIALS AND METHODS: Seventy-two healthy subjects were studied after treatment with topical betaxolol in both eyes. We analyzed ADRB1 and ADRB2 gene polymorphisms by PCR and automated DNA sequencing. RESULTS: There was statistically significant difference between baseline intraocular pressure (IOP) and final IOP of both eyes (baseline IOP 16.2 ± 1.2 - follow-up IOP 13.6 ± 2.0 (mean difference-2.5 ± 1.3, p < 0.001). Gly389 had a higher baseline IOP than Arg389 (17.0 ± 1.2 mmHg versus 16.0 ± 1.2 mmHg; p = 0.02), and conversely Arg389 had a greater magnitude of response than Gly389 to betaxolol therapy (-2.9 ± 1.1 mmHg versus -0.7 ± 0.4 mmHg; p < 0.001). Gln27 had a higher response than Glu27 (-2.7 ± 1.3 mmHg versus -1.9 ± 1.0; p = 0.02). CONCLUSION: Arg389 polymorphism of the ADRB1 gene and Gln27 polymorphism of the ADRB2 gene were associated with the hypotensive response to topic betaxolol in healthy Mexican volunteers.

Long acting betaxolol ocular inserts based on polymer composite.

Poor bioavailability and therapeutic response of conventional therapy due to many pre-corneal constraints necessitate the development of novel controlled and sustained ocular drug delivery to become a standard one in modern pharmaceutical era. This investigation aimed to study the drug release kinetics of betaxolol hydrochloride from a hydrophobic matrix system of PMMA cast with incorporating different proportions of polyethylene oxide (PEO) and evaluate its ability to improve ocular bioavailability and duration of action for the drug. Matrix type ocular inserts were prepared by the film casting technique and characterized in vitro by drug release studies using a flow through apparatus that simulated the eye conditions. All the formulations were subjected to physicochemical evaluation. Rabbit model with steroid induced glaucoma was used to establish in vivo efficacy of inserts. Polymer composition and concentration significantly affected the drug release based on change in diffusional path length and formation of gelaneous pores by polymer erosion. Formulations released the drug by non-fickian diffusion including anomalous transport (0.51). It was also observed that increasing the proportion of PEO in to PMMA does not affect the blend miscibility. IVIVC suggested no significant difference (P< 0.001) between in vitro and in vivo release of drug from inserts. In vivo IOP lowering activity was better for optimized insert F8 (for 24 h) as compared to eye drops (10 h). This ocular insert could be a promising once-a-day sustained release formulation for treating glaucoma.

Betaxolol hydrochloride loaded chitosan nanoparticles for ocular delivery and their anti-glaucoma efficacy.

Many effective anti-glaucoma drugs available for the treatment of ocular hypertension and open angle glaucoma are associated with rapid and extensive precorneal loss caused by the drainage and high tear fluid turnover. The present study involved design of mucoadhesive nanoparticulate carrier system containing betaxolol hydrochloride for ocular delivery to improve its corneal permeability and precorneal residence time. Nanoparticles were prepared by spontaneous emulsification method and had a particle size of 168-260 nm with zeta potential of 25.2-26.4 mV. The in vitro release studies in simulated tear fluid exhibited biphasic release pattern with an initial burst followed by sustained release upto 12 h. The sterility tests confirmed that formulation was free from viable microorganisms and suitable for ocular delivery. The ocular tolerance of nanoparticles was evaluated using Hen Egg-Chorion Allantoic Membrane (HE-CAM) method and was found to be non-irritant. Stability studies of nanoparticles revealed that there was no significant change in particle size and drug content after storage at 25 ± 2°C/60 ± 5% RH over a period of 3 months. In vivo pharmacodynamic studies were carried out in dexamethasone induced glaucoma model in rabbits. The developed nanoparticles showed significant decrease in intraocular pressure (IOP) compared to marketed formulation. Optimized formulation of BN3 showed gradual reduction of IOP reaching peak value of 9.9 ± 0.5mm Hg, equivalent to 36.39 ± 1.84% reduction in IOP compared to control at the end of 5 h which was significant (p < 0.05) compared to marketed formulation. Thus, our studies demonstrate that developed nanoparticles offer a promising delivery system for the management of glaucoma.

Efficacy of combined administration of 0.2% brimonidine and 0.5% betaxolol in treatment of primary open angle glaucoma and ocular hypertension.

PURPOSE: To observe the efficacy of combined use of brimonidine and betaxolol in treatment of primary open angle glaucoma (POAG) and ocular hypertension. METHODS: A total of 54 patients (90 eyes) with POAG and ocular hypertension were randomly divided into three groups (receiving betaxolol, brimonidine and combined administration of betaxolol and brimonidine respectively). The administration was given twice daily in all groups (0.5% betaxolol, 0.2% brimonidine and 0.5% betaxolol combined with 0.2% brimonidine). The changes in intraocular pressure (IOP) were observed before, and 2, 4, 6, and 8 weeks after treatment. In addition, the adverse reactions were also recorded post-treatment. RESULTS: The mean IOPs at all the time points after treatment were significantly reduced compared with pre-treatment levels (P < 0.05). Patients receiving brimonidine had a greater reduction in IOP compared with their counterparts in the betaxolol group but the difference was not statistically significant. The IOP decline was significantly higher in the combined therapy group than in the other two groups (P < 0.01). Few cases presented with slight discomfort, such as sensation of foreign bodies, ocular irritation, dizziness, headache, fatigue, and dryness of mouth and nose. No severe adverse reactions were noted following administration. CONCLUSION: Combined use of brimonidine and betaxolol is an efficacious treatment of reducing IOP without severe side effects.

Effects of argon laser trabeculoplasty in the Early Manifest Glaucoma Trial.

PURPOSE: To analyze reduction of intraocular pressure (IOP) by argon laser trabeculoplasty (ALT) in the Early Manifest Glaucoma Trial and factors influencing the effect of such treatment. DESIGN: Cohort study based on 127 patients from the treatment group of the Early Manifest Glaucoma Trial, a randomized clinical trial. METHODS: Patients randomized to the treatment arm of the Early Manifest Glaucoma Trial received a standard treatment protocol (topical betaxolol hydrochloride followed by 360-degree ALT) and then were followed up prospectively at 3-month intervals for up to 8 years. One eye per patient was included in the analyses. We investigated the relationship between IOP before ALT and subsequent IOP reduction and other factors that might have influenced the effect of ALT, including stage of the disease, trabecular pigmentation, presence of exfoliation syndrome, and treating surgeon. RESULTS: The mean ± standard deviation IOP before ALT and after betaxolol treatment was 18.1 ± 3.9 mm Hg, and the mean ± standard deviation short-term IOP reduction 3 months after ALT was 2.8 ± 3.9 mm Hg (12.6 ± 20.5%). The IOP before ALT strongly affected IOP reduction (P < .001); each 3-mm Hg higher IOP before ALT value was associated with an additional mean IOP reduction of approximately 2 mm Hg. The treating surgeons also had a significant impact on IOP reduction (P = 0.001), with mean values ranging from 5.8 to -1.3 mm Hg. CONCLUSIONS: In this cohort, which included many patients with low IOP levels, IOP before ALT markedly influenced the IOP reduction induced by ALT, seen as a much larger decrease in eyes with higher IOP before ALT. The treating surgeon also had a significant impact on ALT outcome.

Direct intra-accumbal infusion of a beta-adrenergic receptor antagonist abolishes WIN 55,212-2-induced aversion.

The cannabinoid system is known to interact with a variety of neuromodulators in the central nervous system and impacts diverse behaviors. Previous studies have demonstrated that limbic norepinephrine is a critical determinant in the behavioral expression of cannabinoid-induced aversion. The present study was carried out to define the adrenergic receptor subtype involved in mediating cannabinoid-induced behavioral responses. An acute microinjection of the ß1-adrenergic receptor blocker, betaxolol, directly into the nucleus accumbens (Acb), was able to prevent WIN 55,212-2-induced aversion, but not lithium-induced aversion, as measured in a place conditioning paradigm. These results suggest that noradrenergic transmission in the Acb is important for cannabinoid-induced aversion and that beta-adrenergic antagonists may be effective in counteracting negative side effects of cannabinoid-based agents.