Ocular and Systemic Pharmacokinetics of Brimonidine and Timolol After Topical Administration in Rabbits: Comparison Between Fixed-Combination and Single Drugs

Suzuki, Gen; Kunikane, Eriko; Shinno, Keisuke; Kozai, Seiko; Kurata, Masahiro; Kawamura, Akio

doi:10.1007/s40123-020-00229-x

Cited by 10 publications

(6 citation statements)

References 30 publications

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“…While we were unsuccessful in finding pharmacokinetic data on this drug combination, the results of a recent pharmacokinetics study performed on rabbits using eye drops containing a fixed combination of timolol and another antiglaucoma drug (brimonidine) have been published. In this study, the half-life of timolol in plasma following topical administration was approximately 1 h, similar to that of brimonidine [17].…”

Section: Introductionsupporting

confidence: 68%

“…This indicates that hydrolysis of latanoprost at the infusion site either does not occur or, more probably, is only partial, thereby allowing the unhydrolysed lipophilic ester prodrug to escape elimination by the liver and be transported to sites of its pharmacological action through the blood. Most likely, under slow subcutaneous infusion, latanoprost binds to plasma proteins, such as albumin, which considerably affects its pharmacokinetics, as happens with many other drugs [ 23 , 24 ]. Of note, the IOP-lowering effect of the slow subcutaneous infusion of latanoprost reached its maximum only on the third day of uninterrupted infusion.…”

Section: Discussionmentioning

confidence: 99%

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Peripheral Latanoprost Administration Lowers Intraocular Pressure in the Wistar Rat

et al. 2020

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Purpose: Instillation of latanoprost eye drops into the conjunctival sac to lower intraocular pressure (IOP) is the most frequently used treatment for primary open-angle glaucoma. The aim of this study was to evaluate the influence of latanoprost on IOP in the rat when applied peripherally. Methods: A rodent-dedicated tonometer was used to measure IOP in conscious adult male normotensive Wistar rats habituated to the measurement procedure. Commercially available 0.005% latanoprost solutions were continuously delivered to the periphery of the eye over 7 days using mini-pumps inserted subcutaneously in the animal's back, and IOP was measured daily. For comparison, a solution containing an equimolar concentration of latanoprost acid, an active compound of latanoprost, was similarly infused into the eyes of different Wistar rats. Results: Continuous subcutaneous infusion of latanoprost gradually decreased the IOP; the stable nadir of IOP, which was 20% lower than that prior to the start of infusion, was reached on day 3. The effect was statistically significant and fully reversed 2 days after cessation of drug delivery. Continuous subcutaneous application of the solution containing an equimolar amount of latanoprost acid did not appreciably influence the IOP. Conclusion: Subcutaneous continuous delivery of latanoprost decreased the IOP in the conscious normotensive Wistar rats in this study. If this effect is confirmed in humans, it may open the possibility of using peripheral systems of drug delivery, which could significantly improve patient compliance.

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Section: Introductionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Peripheral Latanoprost Administration Lowers Intraocular Pressure in the Wistar Rat

et al. 2020

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“…An animal study comparing the pharmacokinetics of brimonidine and timolol between the fixed-combination and concomitant instillation of two individual drugs showed similar concentrations in the aqueous humor. However, non-interval concomitant instillation resulted in lower concentrations of brimonidine and timolol in the aqueous humor than that with a 5-min interval between instillation of the two individual drugs [ 29 ]. Multiple instillations of eye drops without an appropriate administration interval cause dilution of the drug and reduces its efficiency [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Brimonidine and timolol concentrations in the human vitreous and aqueous humors after topical instillation of a 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution: An interventional study

et al. 2022

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Purpose To evaluate the concentrations of brimonidine and timolol in the vitreous and aqueous humors after instillation of a 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution. Methods This single-arm open-label interventional study included patients with macular holes or idiopathic epiretinal membranes who were scheduled for vitrectomy. Written informed consent was obtained from all participants. A 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution was administered topically twice daily for 1 week preoperatively. The vitreous and aqueous humors were sampled before vitrectomy, and brimonidine and timolol concentrations were quantified using liquid chromatography-tandem spectrometry. This study was registered with the Japan Registry of Clinical Trials (jRCT, ID jRCTs051200008; date of access and registration: April 28, 2020). The study protocol was approved by the University of Fukui Certified Review Board (CRB) and complied with the tenets of the Declaration of Helsinki. Results Eight eyes of eight patients (7 phakic eyes and 1 pseudophakic eye) were included in this study. The mean brimonidine concentrations in the vitreous and aqueous humors were 5.04 ± 4.08 nM and 324 ± 172 nM, respectively. Five of the eight patients had brimonidine concentrations >2 nM in the vitreous humor, which is necessary to activate α2 receptors. The mean timolol concentrations in the vitreous and aqueous humors were 65.6 ± 56.0 nM and 3,160 ± 1,570 nM, respectively. Brimonidine concentrations showed significant positive correlations with timolol concentrations in the vitreous humor (P < 0.0001, R2 = 0.97) and aqueous humor (P < 0.0001, R2 = 0.96). Conclusions The majority of patients who received a 0.1% brimonidine tartrate and 0.5% timolol topical fixed-combination ophthalmic solution showed a brimonidine concentration >2 nM in the vitreous humor. Brimonidine and timolol may be distributed in the ocular tissues through an identical pathway after topical instillation.

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“…In a study of reproductive toxicity, oral administration of 5 mg/kg brimonidine to pregnant rabbits caused abortion in individual rabbits because of uterine contraction, and had no teratogenic effect on offspring [ 4 ]. According to published pharmacokinetic studies [ 22 ], brimonidine is metabolized in the liver and excreted in urine, with a half-life for blood elimination of 3 h and binding rate of 29% for plasma protein. Such experimental conclusions have reference value for the use of brimonidine.…”

Section: Discussionmentioning

confidence: 99%

Preliminary evaluation of the efficacy and safety of brimonidine for general anesthesia

et al. 2021

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Background To determine the hypnotic and analgesic effects of brimonidine, and evaluate its efficacy and safety for general anesthesia. Potentiation of pentobarbital sleeping time following brimonidine administration was observed in mice, as was the analgesic activity of brimonidine. Methods The median effective dose (ED50) and lethal dose (LD50) of intraperitoneally injected brimonidine were determined in hypnotized mice. In addition, the LD50 of intravenously injected brimonidine, and ED50 of intravenously, intramuscularly, and intrarectally injected brimonidine in hypnotized rabbits were determined. Finally, the synergistic anesthetic effect of brimonidine and chloral hydrate was evaluated in rabbits. Results Intraperitoneal injection of 10 mg/kg brimonidine enhanced the hypnotic effect of a threshold dose of pentobarbital. Intraperitoneally injected brimonidine produced dose-related analgesic effects in mice. The ED50 of intraperitoneally administered brimonidine in hypnotized mice was 75.7 mg/kg and the LD50 was 379 mg/kg. ED50 values of intravenous, intramuscular, and intrarectal brimonidine for hypnosis in rabbits were 5.2 mg/kg, 8.8 mg/kg, and 8.7 mg/kg, respectively; the LD50 of intravenous brimonidine was 146 mg/kg. Combined intravenous administration of 0.6 mg/kg brimonidine and 0.03 g/kg chloral hydrate had a synergistic anesthetic effect. Conclusions Brimonidine elicited hypnotic and analgesic effects after systemic administration and exhibited safety. Moreover, brimonidine enhanced the effects of other types of narcotics when combined.

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Ocular and Systemic Pharmacokinetics of Brimonidine and Timolol After Topical Administration in Rabbits: Comparison Between Fixed-Combination and Single Drugs

Cited by 10 publications

References 30 publications

Peripheral Latanoprost Administration Lowers Intraocular Pressure in the Wistar Rat

Peripheral Latanoprost Administration Lowers Intraocular Pressure in the Wistar Rat

Brimonidine and timolol concentrations in the human vitreous and aqueous humors after topical instillation of a 0.1% brimonidine tartrate and 0.5% timolol fixed-combination ophthalmic solution: An interventional study

Preliminary evaluation of the efficacy and safety of brimonidine for general anesthesia

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