Continuous Monitoring of Circadian Variations in Intraocular Pressure by Telemetry System Throughout a 12-Week Treatment with Timolol Maleate in Rabbits

Akaishi, Takahiro; Ishida, Narihiro; Shimazaki, Atsushi; Hara, Hideaki; Kuwayama, Yasuaki

doi:10.1089/jop.2005.21.436

Cited by 23 publications

(21 citation statements)

References 25 publications

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“…After topical application, timolol has been demonstrated to significantly lower IOP in rabbits 3,8,13) and humans. 1) Timolol penetrates mainly through the cornea, which acts as a depot for the drug 18) and permeates predominantly by passive diffusion.…”

Section: Discussionmentioning

confidence: 99%

“…8,9) Briefly, rabbits were anesthetized with an intramuscular injection of 40 mg/kg ketamine plus 4 mg/kg xylazine and also received indomethacin (10 mg/kg intraperitoneally). In addition, 50 ml of 0.1% diclofenac sodium solution and 0.4% oxybuprocaine hydrochloride solution were instilled into the right eye.…”

Section: Animalsmentioning

confidence: 99%

“…8,9) The implanted telemetry transmitter sent IOP information to a receiver (RPC-1; Data Science International), and the information was transferred to a computer-based data-acquisition system through the data-exchange matrix (DEM; Data Science International). Each rabbit's IOP information was measured continuously at 100 Hz for 15 s in cycle runs of 2.5 min and the average value was saved.…”

Section: Animalsmentioning

confidence: 99%

“…As timolol causes the reduction of IOP by suppressing aque- ous humor formation and does not change its outflow, 13) the differential equation of IOP after instillation of timolol can be expressed as follows: (8) An indirect response model 14) is applied for expressing the time delay in the maximum IOP reduction against aqueous humor concentration of timolol. This model represents a general approach where the rate of change in response is controlled by a zero-order process (zero-order rate constant K in ) for production of the response and a first-order process (firstorder rate constant K out ) for loss of the response.…”

Section: )mentioning

confidence: 99%

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Ocular Pharmacokinetic/Pharmacodynamic Modeling for Timolol in Rabbits Using a Telemetry System

Sakanaka

Kawazu

Tomonari

et al. 2008

Biological & Pharmaceutical Bulletin

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We have established an ocular pharmacokinetic/pharmacodynamic (PK/PD) model for a b b-adrenergic antagonist, timolol, after instillation into rabbits. Timolol concentrations were determined by HPLC in the tear fluid, aqueous humor, cornea, and iris-ciliary body after instillation or ocular injection into the anterior chamber of the eye in rabbits. In addition, intraocular pressure (IOP) measurement was performed after instillation of timolol by a telemetry system, which was able to obtain detailed IOP data automatically. The PK/PD parameters were estimated by fitting the concentration-time profiles and the ocular hypotensive effect-time profiles using MULTI (RUNGE) program. The PK model consisted of six compartments and the PD model included aqueous humor dynamics based on an action mechanism of timolol, which causes lowering of IOP by suppressing aqueous humor production. The PK/PD model described well the concentration-time profiles and the ocular hypotensive effect-time profiles after instillation of timolol. This study is the first trial to develop an ocular PK/PD model for timolol after instillation. This model can predict both the drug concentrations in various ocular tissues and the ocular hypotensive effect after instillation of timolol.

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Section: Discussionmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: )mentioning

confidence: 99%

See 2 more Smart Citations

Ocular Pharmacokinetic/Pharmacodynamic Modeling for Timolol in Rabbits Using a Telemetry System

Sakanaka

Kawazu

Tomonari

et al. 2008

Biological & Pharmaceutical Bulletin

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“…8,9) Briefly, the telemetry transmitter (Model TA11PA-C40; Data Science International, St. Paul, MN, U.S.A.) was inserted into a subcutaneous pocket prepared in the cheek of an anesthetized rabbit, and its pressure catheter was tunneled subcutaneously to an exit site near the superior conjunctival sac of the right eye. The sensor catheter was inserted into the midvitreous through a small hole in the sclera, and was tied with nylon sutures.…”

Section: Drug Disposition In Aqueous Humormentioning

confidence: 99%

Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs

Sakanaka

Kawazu

Tomonari

et al. 2008

Biological & Pharmaceutical Bulletin

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The current mainstay of glaucoma treatment is topical medications of ocular hypotensive effect drugs in controlling intraocular pressure (IOP) and preserving visual field. IOP is mainly determined by the aqueous humor dynamics, which is the coupling of aqueous humor formation in the ciliary body and its drainage through the uveoscleral route and the trabecular meshwork route.1) The action mechanisms of anti-glaucoma drugs are well known and classified into several action mechanisms 2,3) : b-adrenergic antagonists (e.g., timolol, betaxolol), carbonic anhydrase inhibitors (e.g., dorzolamide), and a 2 -adrenergic agonists (e.g., apraclonidine, brimonidine) that suppress aqueous humor formation; prostaglandin FP receptor agonists (e.g., latanoprost, travoprost), prostamides (e.g., bimatoprost), and a 1 -adrenergic antagonists (bunazosin), which promote aqueous humor outflow through the uveoscleral route; and cholinomimetics (e.g., pilocarpine) responsible for promoting aqueous humor outflow through the trabecular meshwork route as a result of contraction of the ciliary muscle.It is also a common practice to use multiple anti-glaucoma drugs in combination to achieve target IOP lowering when a favorable response is not obtained by monotherapy. 4) In order to comprehend the result of multidrug treatment, some comparative studies on the combined effects of drugs were reported. 4,5) However, in multidrug therapy, without experiments it has been impossible to determine the strength and duration of the ocular hypotensive effect quantitatively.Pharmacokinetic/pharmacodynamic (PK/PD) models allow us to predict quantitatively both the drug concentration and pharmacological effect after administration of drugs. In the previous reports, we have succeeded in developing two ocular PK/PD models for anti-glaucoma drugs after instillation into rabbits. One is the model for an a 1 -adrenergic antagonist, bunazosin, 6) and the other is for a b-adrenergic antagonist, timolol, 7) but no ocular PK/PD model for multidrug therapy for the eye has been devised. The models for bunazosin and timolol each include aqueous humor dynamics based on each action mechanism, which are different from one another; therefore, a combined ocular PK/PD model after instillation of a combination of multiple drugs must be able to be constructed by including each action mechanism.In the present study, we constructed a new combined ocular PK/PD model by including both the action mechanisms of bunazosin and timolol, and simulated the theoretical drug concentrations and ocular hypotensive effects after instillation of a combination of bunazosin and timolol into rabbits using the combined model and PK/PD parameters for each drug. In addition, to verify the reliability of the combined model, we confirmed the drug concentrations and ocular hypotensive effects measured by a telemetry system after instillation of the drug combination. The PD parameters for bunazosin were recalculated from the ocular hypotensive effects measured by the telemetry system in order to obtain...

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Study Design and Methodologies for Evaluation of Anti-glaucoma Drugs

Miller

2013

Methods in Pharmacology and Toxicology

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A large number of factors are important in conducting anti-glaucoma drug efficacy studies. It is essential to have an understanding of aqueous humor dynamics and how the tonometer, tonometrist, and animal may affect IOP estimates. Additional critical considerations in the design of an anti-glaucoma drug efficacy studies include the following: (1) selecting the most appropriate species, (2) identifying the rate of nonresponders within the study population, (3) determining whether normotensive or glaucomatous animals should be used, and deciding (4) what secondary endpoints (if any) to include, and (5) whether one eye or both should be dosed. Anti-glaucoma drug efficacy studies have an acclimation phase in which the animal becomes conditioned to the procedures, a predose phase in which baseline data is collected, a dosing phase in which the drug is administered and IOP and possibly other endpoints are monitored, and a recovery phase in which IOP returns to predose values as the drug is washed out before another predose phase is started.

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Continuous Monitoring of Circadian Variations in Intraocular Pressure by Telemetry System Throughout a 12-Week Treatment with Timolol Maleate in Rabbits

Cited by 23 publications

References 25 publications

Ocular Pharmacokinetic/Pharmacodynamic Modeling for Timolol in Rabbits Using a Telemetry System

Ocular Pharmacokinetic/Pharmacodynamic Modeling for Timolol in Rabbits Using a Telemetry System

Ocular Pharmacokinetic/Pharmacodynamic Modeling for Multiple Anti-glaucoma Drugs

Study Design and Methodologies for Evaluation of Anti-glaucoma Drugs

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