Distribution of brimonidine into anterior and posterior tissues of monkey, rabbit, and rat eyes.

The objectives of the study were to evaluate the distribution of brimonidine (alpha2-adrenergic agonist) into anterior and posterior ocular tissues. Single or multiple doses of a 0.2 or 0.5% brimonidine tartrate solution were administered to one or both eyes of monkeys or to one eye of rabbits. Brimonidine was administered intraperitoneally to rats. After topical administration, [14C]brimonidine was rapidly absorbed into the cornea and conjunctiva and distributed throughout the eye. [14C]Radioactivity was higher and cleared more slowly in pigmented tissues (iris/ciliary body, choroid/retina, and optic nerve) than in nonpigmented tissues. Single and multiple dosing led to a similar drug distribution, with higher levels of brimonidine measured in pigmented tissues after multiple dosing. Most of the radioactivity extracted from ocular tissues represented unchanged brimonidine. In the rabbits and the monkey treated in only one eye, levels of radioactivity in the untreated eye were low, consistent with the low systemic levels and rapid drug clearance. Posterior ocular tissue concentrations of radioactivity exceeded systemic blood concentrations. The vitreous humor brimonidine concentrations in monkeys treated topically with 0.2% brimonidine tartrate was 82 +/- 45 nM. Vitreous levels in rabbits confirmed the penetration of brimonidine to the posterior segment. Similar concentrations of brimonidine (22 to 390 nM) were measured in the vitreous and retina of rats injected intraperitoneally with brimonidine. Both topically applied and systemically administered brimonidine reach the back of the eye at nanomolar concentrations sufficient to activate alpha2-adrenergic receptors. The brimonidine levels achieved at the retina are relevant for neuroprotection models.     

Preservative-free versus preserved brimonidine %0.15 preparations in the treatment of glaucoma and ocular hypertension: short term evaluation of efficacy,safety, and potential advantages

Abstract

Purpose: To compare the efficacy, safety, and potential advantages of the preservative-free versus preserved brimonidine %0.15 preparations in patients with primer open-angle glaucoma (POAG) or ocular hypertension (OHT).

Methods: Forty-two eyes of the 21 treatment-naive patients with POAG or OHT were enrolled in this study. Eyes were randomly assigned to receive brimonidine-purite 0.15% or preservative-free brimonidine 0.15% two times daily. Efficacy of the two eye drops was assessed by measuring the intraocular pressure (IOP) at 9–10 am at baseline and week 4. Safety and potential advantages of the drops were evaluated at weeks 4 in terms of ocular symptoms and tear parameters. Ocular symptom values of the patients were evaluated with a scale of 0–4 (0?=?no discomfort and 4?=?severe discomfort).

Results: Both of the brimonidine tartrate formulations resulted in statistically similar IOP reduction (preserved formulation; ?5.2?mmHg [22.9% reduction] preservative-free formulation; ?5.7?mmHg [24.1% reduction], p?=?0.37). It was found that brimonidine tartrate formulations with and without topical preservatives did not produce a statistically significant difference in pain, stinging, and blurred vision at the upon instillation (p?>?0.05). However, the burning sensation was significantly higher in the preservative-free formulation at the first instillation compared to the preserved formulation (p?=?0.01). Also, there was no statistically significant difference between the two formulations in terms of symptoms (itching, burning, tearing, stinging, and photophobia) and tear parameters during the day (p?>?0.05).

Conclusions: Although topical preservative-free brimonidine tartrate treated eyes had a more burning sensation at the first drop, the two formulations were similar in terms of ocular tolerability in the short term period. Also, both formulations were found to reduce IOP at a similar rate.     

Brimonidine purite 0.1% versus brinzolamide 1% as adjunctive therapy to latanoprost in patients with glaucoma or ocular hypertension

ABSTRACT

Objective: To evaluate the efficacy and tolerability of brimonidine purite 0.1% in comparison to brinzolamide 1% when used as adjunctive therapy to latanoprost 0.005% in patients with glaucoma or ocular hypertension.

Methods: Randomized, single-center, investigator-masked, parallel-group clinical study. Patients with IOP?≥?18?mmHg while on once-daily latanoprost were randomized to adjunctive treatment with brimonidine purite TID (n?=?20) or brinzolamide TID (n?=?20) for 3 months. Intraocular pressure (IOP) was measured at 8 a.m., 10 a.m., and 4 p.m. at latanoprost-treated baseline and after 1 and 3 months of latanoprost and adjunctive therapy. A patient questionnaire was administered to evaluate the tolerability of eye drop instillation.

Results: Baseline mean diurnal IOP (± standard deviation, mmHg) on latanoprost was comparable between groups (brimonidine purite: 19.6?±?2.94; brinzolamide: 19.8?±?3.25; p = 0.846). Mean diurnal IOP at Month 3 was 16.3?±?2.63?mmHg with brimonidine purite and 17.8?±?2.19?mmHg with brinzolamide (?p = 0.028). Adjunctive use of brimonidine purite provided greater IOP lowering than brinzolamide at 10 a.m. (?p < 0.001) and 4 p.m. (?p = 0.050) and equivalent IOP lowering to brinzolamide at 8 a.m. (?p = 0.716). Blurred vision at Month 1 and bitter taste at Months 1 and 3 were more common upon instillation of brinzolamide eye drops.

Conclusion: Brimonidine purite 0.1% provided significantly lower IOP compared with brinzolamide 1% when used as adjunctive therapy to latanoprost. Both adjunctive therapies were well tolerated. Limitations of this study include the use of a single site and the sample size. Additional studies are needed to further evaluate these drugs as adjunctive therapy to prostaglandin analogs.     

Topical brimonidine 0.2%/timolol 0.5% ophthalmic solution: in glaucoma and ocular hypertension

A fixed combination of brimonidine (a highly selective alpha(2)-adrenergic agonist) and timolol (a non-selective beta-blocker) [brimonidine 0.2%/timolol 0.5% ophthalmic solution; brimonidine/timolol] is available for the topical treatment of glaucoma and ocular hypertension (OH). Brimonidine and timolol decrease elevated intraocular pressure (IOP) by complementary mechanisms of action and have an additive effect when coadministered to healthy volunteers and patients with glaucoma or OH. When assessed over a 3- or 12-month period in large, well designed clinical studies, brimonidine/timolol instilled twice daily (one drop in each eye) was superior to monotherapy with the individual components instilled two (brimonidine) or three (timolol) times daily, and noninferior to concomitant therapy with the individual components instilled twice daily, in lowering raised IOP in patients with glaucoma or OH. In small, randomised, comparative studies of 1 or 3 months' duration, the IOP-lowering effect of brimonidine/timolol twice daily was similar or superior to that of fixed combination dorzolamide 2%/timolol 0.5% ophthalmic solution (dorzolamide/timolol) twice daily (preliminary data). Brimonidine/timolol is generally well tolerated with a predictable local and systemic adverse event profile based on that of the individual components used alone and concomitantly. No unexpected or serious adverse events associated with the fixed combination were reported in key clinical trials. Brimonidine/timolol may be advantageous over dorzolamide/timolol with respect to ocular tolerability and comfort (preliminary data).     

The evolving pharmacotherapeutic profile of brimonidine,an 2-adrenergic agonist,after four years of continuous use

Since its introduction in 1996, use of brimonidine tartrate 0.2% ophthalmic solution (Alphagan^®, Allergan), a highly selective ₂-adrenergic agonist, has become increasingly popular for the initial and long-term management of ocular hypertension and glaucoma. Recently, ongoing clinical comparison trials of up to three years in length have reported sustained intraocular pressure (IOP) lowering efficacy with brimonidine 0.2% b.i.d., which was comparable with timolol 0.5% (Timoptic^®; Merck & Co.), accompanied by a favourable tolerability and safety profile. Also, many post-market studies have demonstrated the utility of brimonidine 0.2% b.i.d. as mono- and adjunctive therapy. Furthermore, major inroads have been made in the study of other possible pharmacotherapeutic benefits of brimonidine treatment, namely the potential for neuroprotection. This review will present a brief developmental history and examine key pharmacotherapeutic characteristics of brimonidine, including its receptor selectivity, IOP-lowering mechanism of action and potential neuroprotective activities. Moreover, the literature on brimonidine’s efficacy and safety profiles in the treatment of ocular hypertension and glaucoma will be perused, and new four-year data from an ongoing double-masked clinical study comparing brimonidine tartrate 0.2% with timolol 0.5%, b.i.d will be introduced. Brimonidine 0.2% b.i.d. provided sustained IOP-lowering efficacy comparable to timolol 0.5% b.i.d., with no significant differences at trough or peak during year four of continuous use. Visual fields were well preserved in both treatment groups with 93% of brimonidine patients and 91% of timolol patients showing no change or improvement. Brimonidine continued to appear safe and well-tolerated, with no clinically significant effects on mean heart rate or blood pressure, and no serious drug-related adverse events (AEs). Two out of 36 brimonidine patients developed ocular allergy; both were resolved without sequelae. Overall post-market surveillance found no reports of unexpected or serious drug-related AEs. These long-term results, in conjunction with those reported in the literature, suggest that brimonidine 0.2% b.i.d. is a highly appropriate first- and second-line therapy for long-term management of glaucoma and ocular hypertension. Potential neuroprotective effects of brimonidine therapy, which might provide additional vision sparing benefit, although supported by compelling animal studies, await clinical verification.     

Fluorimetric Quantification of Brimonidine Tartrate in Eye Drops

A simple and sensitive spectrofluorimetric method has been developed for the estimation of brimonidine tartrate in pure and eye drops. Linearity was obeyed in the range of 0.2-3.0 ΅g/ml in dimethyl formamide as solvent at an emission wavelength (λ_em) of 530 nm after excitation wavelength (λ_ex) of 389 nm with good correlation coefficient of 0.998. The limit of detection and limit of quantification for this method were 22.0 and 72.0 ng/ml, respectively. The developed method was statistically validated as per International Conference on Harmonisation guidelines. The percentage relative standard deviation values were found to be less than 2 for accuracy and precision studies. The results obtained were in good agreement with the labelled amounts of the marketed formulations. The proposed method was effectively applied to routine quality control analysis of brimonidine tartrate in their eye drops.     

The evolving pharmacotherapeutic profile of brimonidine, an alpha 2-adrenergic agonist, after four years of continuous use

Since its introduction in 1996, use of brimonidine tartrate 0.2% ophthalmic solution (Alphagan, Allergan), a highly selective alpha 2-adrenergic agonist, has become increasingly popular for the initial and long-term management of ocular hypertension and glaucoma. Recently, ongoing clinical comparison trials of up to three years in length have reported sustained intraocular pressure (IOP) lowering efficacy with brimonidine 0.2% b.i.d., which was comparable with timolol 0.5% (Timoptic; Merck & Co.), accompanied by a favourable tolerability and safety profile. Also, many post-market studies have demonstrated the utility of brimonidine 0.2% b.i.d. as mono- and adjunctive therapy. Furthermore, major inroads have been made in the study of other possible pharmacotherapeutic benefits of brimonidine treatment, namely the potential for neuroprotection. This review will present a brief developmental history and examine key pharmacotherapeutic characteristics of brimonidine, including its receptor selectivity, IOP-lowering mechanism of action and potential neuroprotective activities. Moreover, the literature on brimonidine's efficacy and safety profiles in the treatment of ocular hypertension and glaucoma will be perused, and new four-year data from an ongoing double-masked clinical study comparing brimonidine tartrate 0.2% with timolol 0.5%, b.i.d. will be introduced. Brimonidine 0.2% b.i.d. provided sustained IOP-lowering efficacy comparable to timolol 0.5% b.i.d., with no significant differences at trough or peak during year four of continuous use. Visual fields were well preserved in both treatment groups with 93% of brimonidine patients and 91% of timolol patients showing no change or improvement. Brimonidine continued to appear safe and well-tolerated, with no clinically significant effects on mean heart rate or blood pressure, and no serious drug-related adverse events (AEs). Two out of 36 brimonidine patients developed ocular allergy; both were resolved without sequelae. Overall post-market surveillance found no reports of unexpected or serious drug-related AEs. These long-term results, in conjunction with those reported in the literature, suggest that brimonidine 0.2% b.i.d. is a highly appropriate first- and second-line therapy for long-term management of glaucoma and ocular hypertension. Potential neuroprotective effects of brimonidine therapy, which might provide additional vision sparing benefit, although supported by compelling animal studies, await clinical verification.     

Daily variation and effects of ambient light and circadian factors on the human light reflex.

Measures of pupillary size and the dynamic light reflex are safe and noninvasive methods to quantify and characterize the mechanism and site of drug action. The effects of variations in ambient light and time of day on pupillary measures were determined. In dark adapted volunteers (n = 13), ambient light was incrementally increased at < 0.1, 4, 40, 100 and 200 foot-candle (ftcd). Subjects adjusted to each light level for 1 min before the light reflex was elicited. Replicate measures were collected with the contralateral eye open and covered with an opaque patch. Data were collected every 3 h between 6 a.m. and 9 p.m. The prestimulus diameter of the dark adapted pupil averaged 6.4 mm at < 0.1 ftcd and 2.3 mm at 200 ftcd. Constriction amplitude decreased with increases in ambient light from 2.1 mm (< 0.1 ftcd) to 0.2 mm (200 ftcd) while constriction and dilatation velocities decreased from 7.7 to 2.8 mm/sec and 4.3 to 2.8 mm/sec, respectively. Time of day effects were small but statistically significant and the interaction of ambient light and time of recording suggests the pupil is differentially sensitive to ambient and phasic light stimuli over the course of the day. A patch over the contralateral eye increased pupil size and velocities of the light reflex. In a second study, 10 volunteers were tested twice a day at 4 and 80 ftcd for four days. While there was wide between subject variability, the within subject differences were small. Such baseline data may be useful in describing the normal variations in these increasingly popular indices of drug action.     

A comparison of the fourth-generation fluoroquinolones gatifloxacin 0.3% and moxifloxacin 0.5% in terms of ocular tolerability

SUMMARY

Purpose: To compare the ocular tolerability of the commercially available ophthalmic solutions of the fourth-generation fluoroquinolones, gatifloxacin 0.3% (Zymart, Allergan, Inc., Irvine, CA) with benzalkonium chloride (BAK) and moxifloxacin 0.5% (Vigamoxt) without BAK.

Methods: A baseline evaluation was conducted on 30 healthy volunteers for conjunctival hyperemia, conjunctival vascularity, pupil size, and anterior chamber (AC) cell and flare. Pupils were measured under scotopic conditions with a Colvard pupillometer. Conjunctival hyperemia and vascularity, and AC reaction were measured on a Likert-like scale of 0-3. Subjects then received drops in both eyes from masked bottles of gatifloxacin ophthalmic solution 0.3% with BAK (in one eye determined randomly) and moxifloxacin ophthalmic solution 0.5% without BAK (in the contralateral eye) in a double-masked fashion. Subjects graded pain and ocular irritation in each eye on a scale of 1-10 after 5min with their eyes closed. The examination was then repeated.

Results: The average age of this study population was 34.4years. The groups of eyes receiving moxifloxacin 0.5% demonstrated an increase in mean conjunctival hyperemia (0.21 [range: 0-1] at baseline to 1.52 [range: 0-3] at 5min.)

that was significantly greater (p?=?0.0005) compared with that of the group receiving gatifloxacin 0.3% (0.22 [range: 0-1] at baseline to 0.45 [range: 0-2] at 5min). The group receiving moxifloxacin 0.5% showed an increase in conjunctival vascularity (0.55 [range: 0-1] at baseline to 1.61 [range: 0.5-3] at 5?min.) that was significantly greater (p?=?0.0005) compared with that of the group receiving gatifloxacin 0.3% (0.52 [range: 0-1] at baseline to 0.68 [range: 0-2] at 5?min.). Significantly less pain (1.2 vs. 3.2, p?=?0.001) and irritation (0.64 vs. 3.42, p?=?0.001) occurred with gatifloxacin 0.3% than with moxifloxacin 0.5%. Pupil size was significantly reduced (5.65mm-5.05mm) in eyes receiving moxifloxacin 0.5% (p?=?0.004) and no significant change occurred in pupil size (5.60mm-5.65mm) in eyes that received gatifloxacin 0.3% (p?=?0.878). No AC reaction was noted with either medication.

Conclusions: The group of eyes receiving gatifloxacin 0.3% with BAK demonstrated greater ocular tolerability in comparison to the group receiving moxifloxacin 0.5% without BAK. Moxifloxacin-induced pupillary miosis may be due to prostaglandin release in the anterior chamber. A limitation of this study is the relatively young age of the study population.     

Treatment of patients with primary open-angle glaucoma with a fixed combination of brimonidine 0.2%/timolol 0.5%: multicenter,open-label,observational study in Germany*

ABSTRACT

Objective: At the introduction of the fixed-combination of brimonidine/timolol in Germany in 2006, a non-interventional, multicenter, observational, open-label study was initiated to evaluate efficacy, tolerability, and safety of this preparation in a broad patient population.

Methods: The study population comprised patients with bilateral primary open-angle glaucoma or ocular hypertension with insufficient intraocular pressure (IOP) control who participating physicians determined required a change of medication, and who switched to exclusive use of the new fixed-combination brimonidine 0.2%/timolol 0.5%. Patient demographics and information on specific risk factors were collected. IOP readings were recorded for each eye at treated baseline (previous therapy), 4 to 6 weeks, and 12 weeks after changing to twice-daily brimonidine/timolol. Tolerability was measured using a four-step scale ranging from excellent to poor. All adverse events were recorded.

Results: Mean treated baseline IOP (±SD) for all patients (N?=?861) was 20.8?±?3.5?mmHg. Five hundred sixty-five patients switched from monotherapy, 138 patients switched from other fixed combinations, and 158 patients had been using non-fixed combinations of up to four different active agents. The brimonidine/timolol fixed combination provided an additional IOP decrease in most pretreatment subgroups, with an overall reduction to 16.9?±?2.6?mmHg after 4 to 6 weeks and to 16.5?±?2.7?mmHg after 12 weeks. Both of these values were significantly lower than baseline IOP (p?<?0.001). A target pressure of <18?mmHg was achieved in 79.5% of all eyes at week 12. Tolerability of fixed-combination brimonidine/timolol was rated excellent or good by the physicians for 97.1% of patients, and by 93.4% of the patients themselves. Few adverse events occurred during the treatment period.

Conclusions: Although this study was limited by its observational design, our results show that the fixed combination of brimonidine 0.2%/timolol 0.5% was effective, well tolerated, and safe in a broad POAG patient population.     

糖尿病视网膜病变患者围手术期散瞳策略

目的：探讨糖尿病视网膜病变患者围手术期最佳散瞳方法,以利于玻璃体切割手术顺利进行。方法：回顾性分析我院2007年6月-2011年6月所有糖尿病视网膜病变患者的手术资料,选取术前常规应用复方托吡卡胺滴眼液、术中瞳孔直径≥7mm的患者手术时散瞳药的应用记录,共189例,204眼。术前点复方托吡卡胺滴眼液,每5min1次,共6次。点滴眼液后,0.5h内瞳孔散大（直径≥7mm）者为A组（78眼）;超过0.5h,但瞳孔散大时间在1h以内者为B组（75眼）;瞳孔散大时间大于1h者为C组（51眼）。B、C组于术前一天随机应用硫酸阿托品眼用凝胶或盐酸环喷托酯滴眼液,术前1h频点复方托吡卡胺滴眼液。结果：术中瞳孔直径能维持≥7mm的眼数比例,B、C组应用硫酸阿托品眼用凝胶者与应用盐酸环喷托酯滴眼液者差异均无统计学意义（P〉0.5）。术中有134眼因白内障同时行超声乳化白内障摘除术,其术中瞳孔直径能维持≥7mm的眼数比例,B组应用盐酸环喷托酯滴眼液者瞳孔维持的比例较用硫酸阿托品眼用凝胶者高（P〈0.5）,C组中二者比较差异无统计学意义（P〉0.5）。结论：对于术前单用复方托吡卡胺滴眼液散瞳时间超过0.5h者,术前点硫酸阿托品眼用凝胶或盐酸环喷托酯滴眼液有利于维持术中瞳孔大小,且二者效果差异无统计学意义。     

Acute local irritative effect of (2'R)-4'-O-tetrahydropyranyladriamycin, a new antitumor antibiotic

(2"R)-4'-O-Tetrahydropyranyladriamycin hydrochloride (THP), a new antitumor antibiotic, was administered to rabbits at a concentration from 0.02 to 0.5% by instillation, or by intracutaneous, subcutaneous or intramuscular injection to study its local irritative effect. The irritative effect of THP increased with concentration. At a concentration of 0.5%, THP was irritant to the eye, skin and muscle but at a concentration of 0.1% practically no effect was observed. The effect was equal to or lower than that of doxorubicin. An instillation of 0.5% THP caused reversible irritation effect on the eye. Slight conjunctival responses (redness and chemoisis) were observed. Rinsing reduced the irritative effect. Intracutaneous injection of 0.1 ml of 0.5% THP caused well defined, moderate erythema, surface ulceration and dermal necrosis. Cutaneous muscle necrosis also occurred. At a concentration of 0.02%, dermal necrosis and inflammatory cell infiltration were observed. Erythema, as well as muscle necrosis and calcification with giant cell reaction and inflammatory cell infiltration were observed by an intramuscular injection at a concentration of 0.5%. Subcutaneous injection of 0.5% THP showed no irritative effect.     

A comparison of the fourth-generation fluoroquinolones gatifloxacin 0.3% and moxifloxacin 0.5% in terms of ocular tolerability

PURPOSE: To compare the ocular tolerability of the commercially available ophthalmic solutions of the fourth-generation fluoroquinolones, gatifloxacin 0.3% (Zymar, Allergan, Inc., Irvine, CA) with benzalkonium chloride (BAK) and moxifloxacin 0.5% (Vigamox) without BAK. METHODS: A baseline evaluation was conducted on 30 healthy volunteers for conjunctival hyperemia, conjunctival vascularity, pupil size, and anterior chamber (AC) cell and flare. Pupils were measured under scotopic conditions with a Colvard pupillometer. Conjunctival hyperemia and vascularity, and AC reaction were measured on a Likert-like scale of 0-3. Subjects then received drops in both eyes from masked bottles of gatifloxacin ophthalmic solution 0.3% with BAK (in one eye determined randomly) and moxifloxacin ophthalmic solution 0.5% without BAK (in the contralateral eye) in a double-masked fashion. Subjects graded pain and ocular irritation in each eye on a scale of 1-10 after 5 min with their eyes closed. The examination was then repeated. RESULTS: The average age of this study population was 34.4 years. The groups of eyes receiving moxifloxacin 0.5% demonstrated an increase in mean conjunctival hyperemia (0.21 [range: 0-1] at baseline to 1.52 [range: 0-3] at 5 min.) that was significantly greater (p = 0.0005) compared with that of the group receiving gatifloxacin 0.3% (0.22 [range: 0-1] at baseline to 0.45 [range: 0-2] at 5 min). The group receiving moxifloxacin 0.5% showed an increase in conjunctival vascularity (0.55 [range: 0-1] at baseline to 1.61 [range: 0.5-3] at 5 min.) that was significantly greater (p = 0.0005) compared with that of the group receiving gatifloxacin 0.3% (0.52 [range: 0-1] at baseline to 0.68 [range: 0-2] at 5 min.). Significantly less pain (1.2 vs. 3.2, p = 0.001) and irritation (0.64 vs. 3.42, p = 0.001) occurred with gatifloxacin 0.3% than with moxifloxacin 0.5%. Pupil size was significantly reduced (5.65 mm-5.05 mm) in eyes receiving moxifloxacin 0.5% (p = 0.004) and no significant change occurred in pupil size (5.60 mm-5.65 mm) in eyes that received gatifloxacin 0.3% (p = 0.878). No AC reaction was noted with either medication. CONCLUSIONS: The group of eyes receiving gatifloxacin 0.3% with BAK demonstrated greater ocular tolerability in comparison to the group receiving moxifloxacin 0.5% without BAK. Moxifloxacin-induced pupillary miosis may be due to prostaglandin release in the anterior chamber. A limitation of this study is the relatively young age of the study population.     

Evaluation of the effect of thymoxamine solution 0.5% on mydriasis induced by ibopamine solution 1%

Summary The effects of thymoxamine 0.5% solution and of a placebo solution (mannitol) on the mydriasis induced by ibopamine 1% solution were evaluated in 8 healthy volunteers and 12 patients with eye diseases.One drop of ibopamine was instilled into each eye and 30 min later 1 drop of thymoxamine was instilled into one eye and 1 drop of placebo into the contralateral eye. Pupillary diameter was measured before and 30 min after the instillation of ibopamine, immediately before the treatment with thymoxamine and placebo and 30, 60 and 90 min after the instillation of thymoxamine or of placebo.Within 30 min of treatment, ibopamine had produced a statistically and clinically significant mydriatic effect. In eyes treated with thymoxamine, prompt reversal of mydriasis was observed, the baseline diameter being observed within 60 min.No difference in the time-course of the mydriatic effect was detected between healthy subjects and patients. The pupillary response to thymoxamine was not influenced by the colour of the iris. The tolerability of ibopamine and of thymoxamine was good. No local or systemic adverse events were seen or reported.     

Clinical effects of brimonidine ophthalmic drops ingestion in 52 dogs

Brimonidine is an ophthalmic solution of 0.2% brimonidine tartrate used to lower intraocular pressure in human glaucoma patients. A retrospective study was conducted of brimonidine ophthalmic solution ingestion in 52 dogs reported to the ASPCA Animal Poison Control Center between January 1998 and December 2000. Eighty percent of the dogs were < 1-y of age. Approximate ingested dosages ranged from 0.18-5.55 mg/kg. Incidence of clinical signs were bradycardia (67%), depression (46%), ataxia (27%), hypotension (25%), pallor (23%), weakness (17%), change in mucous membrane color (17%), hypothermia (13%), vomiting or retching (13%.). Shock, weak pulses, and poor capillary refill time were also reported. Treatment involved early decontamination, supportive care, andyohimbine and atipamezole as specific alpha-2 antagonists that could be helpful in reversing the effects of brimonidine. Due to the possibility of severe cardiovascular effects developing, the ingestion of brimonidine ophthalmic solution in dogs should be considered dangerous.     

Measurement of brimonidine concentrations in human plasma by a highly sensitive gas chromatography/mass spectrometric assay

Brimonidine is an α₂-adrenergic agonist that is efficacious in lowering intraocular pressure in humans. A highly sensitive and selective gas chromatography/mass spectrometry (GC/MS) assay is described for quantitation of brimonidine in human plasma following ocular installation. Brimonidine in 1 ml of plasma was extracted together with tetradeuterated brimonidine (internal standard) and clonidine (carrier) by solvent extraction. After solvent evaporation, 3,5-bis(trifluoromethyl)benzoyl derivatives were formed and injected onto a GC/MS appartus under negative chemical ionization conditions. The ions monitored for derivatized brimonidine and tetradeuterated brimonidine were m/z 691 [M - HBr] and m/z 694 [M - DBr], respectively. Calibration curves were linear from 2 to 1000 pg ml⁻¹ (r² = 0.981-0.996). The method was specific for brimonidine relative to endogenous compounds in plasma. The inter-day relative standard deviation for analysis of quality controls was 12% or less, and the inter-day assay accuracy ranged from 97 to 104% of nominals. The GC/MS assay showed adequate sensitivity for analysis of human samples from volunteers ocularly dosed with 0.5% brimonidine tartrate solution. Overall, the GC/MS assay showed excellent precision and accuracy, and a minimum quantifiable concentration of 2 pg ml⁻¹.     

Comparison of the effects of clonidine and yohimbine on pupillary diameter at different illumination levels

AIMS: To evaluate the pupillary effects of single doses of the alpha2-adrenoceptor agonist clonidine and the alpha2-adrenoceptor antagonist yohimbine under several illumination conditions. METHODS: Sixteen healthy male volunteers received clonidine 0.2 mg, yohimbine 22 mg, clonidine 0.2 mg + yohimbine 22 mg in a double-blind placebo-controlled, cross-over study. 2 h post drug ingestion pupil diameter was recorded in darkness, and at luminance levels of 6 Cd m-2, 91 Cd m-2 and 360 Cd m-2. The effects of the active treatments on pupil diameter were also expressed as the differences from the placebo condition ('placebo-corrected' data; mean [95% CI]). RESULTS: Clonidine had little effect on pupil diameter in darkness; however, it caused a significant, light-dependent, miosis when the eye was illuminated. On the other hand yohimbine increased pupil size; this increase was significant at 91 and 360 Cd m-2. There were no significant differences between the effects of the combined treatment (clonidine 0.2 mg + yohimbine 22 mg) and the effect of placebo. CONCLUSIONS: The pupillary effects of clonidine and yohimbine are likely to reflect the interaction of these drugs with inhibitory alpha2-adrenoceptors located on central noradrenergic neurones, which in turn would lead to a decrease and an increase, respectively, in sympathetic outflow to the iris. The light dependence of the pupillary effects of these drugs, however, suggests that the parasympathetic light reflex pathway is also involved, which is known to be under inhibitory control from the central noradrenergic neurones. Modulation of parasympathetic outflow seems to play an important role since both drugs had relatively little effect on pupil diameter in darkness when sympathetic activity predominates.     

Efficacy and comfort of olopatadine 0.2% versus epinastine 0.05% ophthalmic solution for treating itching and redness induced by conjunctival allergen challenge

ABSTRACT

Background: Olopatadine 0.2% (Pataday, Alcon Laboratories Inc., Fort Worth, Texas, USA) and epinastine 0.05% (Elestat, Inspire Pharmaceuticals, Inc., Durham, NC, USA) are topical ocular anti-allergic agents. Both are H₁ antihistamine/mast cell stabilizers indicated for the treatment of ocular itching associated with allergic conjunctivitis.

Objective: To compare the efficacy and comfort of olopatadine 0.2% with epinastine 0.05%, in the prevention of ocular itching associated with allergic conjunctivitis following conjunctival allergen challenge (CAC).

Research design and methods: This was a 7 week, four visit, double-masked, randomized, placebo-controlled CAC study. Visit 1 screened subjects for positive ocular allergic responses and Visit 2 confirmed those responses. At Visit 3, 92 subjects were randomized into one of four treatment groups to receive one drop of study medication in each eye: (1) olopatadine 0.2%/placebo, (2) epinastine 0.05%/placebo, (3) olopatadine 0.2%/epinastine 0.05%, (4) placebo/placebo. Subjects were challenged 12?h after drop instillation to evaluate duration of action. At Visit 4, subjects were challenged 5?min after drop instillation to evaluate onset of action. Drop comfort was assessed at Visit 4.

Main outcome measures; results: This article focuses on the results of the onset-of-action challenge (Visit 4). At Visit 4, ocular itching was assessed at 3, 5, and 7?min and redness was assessed at 7, 15, and 20?min post-challenge. Drop comfort was assessed upon instillation, at 30?s, and at 1, 2, and 5?min post-instillation. Olopatadine 0.2%-treated eyes exhibited significantly lower mean ocular itching scores versus epinastine 0.05%-treated eyes at 5 (?p = 0.024) and 7?min (?p = 0.003) post-challenge. Olopatadine 0.2%-treated eyes exhibited significantly lower mean redness scores versus epinastine 0.05%-treated eyes at all time points post-challenge (ciliary: p ≤ 0.013, conjunctival: p ≤ 0.015, episcleral: p ≤ 0.006). Olopatadine 0.2% was rated as significantly more comfortable than epinastine 0.05% at 1?min post-drop instillation (?p = 0.003). All adverse events were non-serious and unrelated to study medication. Although the CAC model reproduces allergic responses that are not environmentally-induced, patients experience varying severities of responses as are seen in real-world situations.

Conclusion: Olopatadine 0.2% was superior to epinastine 0.05% in preventing ocular itching and redness at onset when induced by the CAC model.     

Brimonidine and brinzolamide for treating glaucoma and ocular hypertension; a safety evaluation

Introduction: Brimonidine tartrate and brinzolamide eye drops are often used as third and fourth line treatment options to reduce intraocular pressure (IOP) in the management of glaucoma and ocular hypertension. Better tolerated, more effective topical agents requiring once daily instillation including prostaglandin analogues and beta-blockers usually are preferred as initial therapy, unless there are contraindications. Brimonidine and brinzolamide are often required owing to progressive glaucoma or intolerances to or ineffectiveness of front-line agents.

Areas covered: We review the safety of formulations containing brimonidine tartrate and/or brinzolamide. Safety considerations for these agents in higher risk populations are highlighted.

Expert opinion: Each class of ocular hypotensive eye drop has a unique set of possible side effects. Brimonidine might have neuro-protective capabilities and offer reasonable IOP control, but its use is limited by a relatively high rate of ocular allergy, hyperemia and discomfort. Brinzolamide is generally well tolerated, but often lacks efficacy. The introduction of brimonidine/brinzolamide fixed combination suspension improves adherence (by simplifying the medical regimen) and reduces preservative load on the ocular surface. New drug delivery systems incorporating brimonidine and brinzolamide are in development and promise to improve the safety profiles of both drugs.     

The effect of 0.25% and 0.5% pindolol on intraocular pressure in normal human volunteers

Summary

A study was carried out in 12 healthy volunteers to determine the effects of 0.2.5% and 0.5% pindolol eye drops on intraocular pressure. The results showed that both concentrations produced similar and highly significant falls in intraocular pressure after single instillation into the conjunctival sacs, the effect being measured with a non-contact tonometer. No significant changes were found in resting heart rate.