Beta‐adrenoceptor blocking effects and pharmacokinetics of betaxolol (SL 75212) in man.

Jf, Giudicelli; Chauvin, M.; Thuillez, Christian; Richer, Christine; Bianchetti, G.; Goméni, Roberto; Pl, Morselli

doi:10.1111/j.1365-2125.1980.tb00500.x

Cited by 53 publications

(8 citation statements)

References 19 publications

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“…For multi-MPS platform II they were: betaxolol 37 , linezolid 38 , pindolol 39 , prednisolone 40 , quinidine 41 , ranitidine 42 , theophylline 43 and timolol 44 .…”

Section: Methodsmentioning

confidence: 99%

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

Maaß

Stokes²,

Griffith

et al. 2017

Integr. Biol.

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Microphysiological systems (MPS) provide relevant physiological environments in vitro for studies of pharmacokinetics, pharmacodynamics and biological mechanisms for translational research. Designing multi-MPS platforms is essential to study multi-organ systems. Typical design approaches, including direct and allometric scaling, scale each MPS individually and are based on relative sizes not function. This study’s aim was to develop a new multi-functional scaling approach for integrated multi-MPS platform design for specific applications. We developed an optimization approach using mechanistic modeling and specification of an objective that considered multiple MPS functions, e.g., drug absorption and metabolism, simultaneously to identify system design parameters. This approach informed the design of two hypothetical multi-MPS platforms consisting of gut and liver (multi-MPS platform I) and gut, liver and kidney (multi-MPS platform II) to recapitulate in vivo drug exposures in vitro. This allows establishment of clinically relevant drug exposure-response relationships, a prerequisite for efficacy and toxicology assessment. Design parameters resulting from multi-functional scaling were compared to designs based on direct and allometric scaling. Human plasma time-concentration profiles of eight drugs were used to inform the designs, and profiles of an additional five drugs were calculated to test the designed platforms on an independent set. Multi-functional scaling yielded exposure times in good agreement with in vivo data, while direct and allometric scaling approaches resulted in short exposure durations. Multi-functional scaling allows appropriate scaling from in vivo to in vitro of multi-MPS platforms, and in the cases studied provides designs that better mimic in vivo exposures than standard MPS scaling methods.

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“…For multi-MPS platform II they were: betaxolol 37 , linezolid 38 , pindolol 39 , prednisolone 40 , quinidine 41 , ranitidine 42 , theophylline 43 and timolol 44 .…”

Section: Methodsmentioning

confidence: 99%

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

Maaß

Stokes²,

Griffith

et al. 2017

Integr. Biol.

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“…These six β-blockers possess intrinsic sympathomimetic activity (ISA) [10][11][12], indicating that they are in fact, like xamoterol, partial β-adrenergic agonists. The remaining compounds do not possess ISA [12][13][14][15], demonstrating that the preparation is extremely sensitive in distinguishing compounds with or without ISA.…”

Section: Hts Methodologymentioning

confidence: 99%

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

Sube¹,

Ertel²

2017

JBiSE

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Introduction: Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) form spontaneously beating syncytia in-vitro. We evaluated whether hiPSC-CM are a compelling model of human cardiac pharmacology useful for early drug development. Methods: We measured hiPSC-CM beating frequency using Ca-sensitive dyes and a high-throughput screening system. We quantified the effects of 640 drugs with various structures and pharmacologies. Results: When tested at 1 µM, most drugs without direct effects on heart rhythm or with effects at high concentrations do not change frequency, indicating specificity. In contrast, the preparation detects compounds with direct activity on heart rhythm, demonstrating sensitivity. In particular, β-adrenergic agonists increase frequency and the model differentiates β2 from β1 agonists, as well as partial from full agonists. Phosphodiesterase inhibitors have subtype-specific actions and PDE4 is particularly important in controlling frequency. The preparation is sensitive to cardiac ion channel blockers: L-type calcium channel blockers, Class-I and Class-III antiarrhythmics change frequency but drugs acting on K ATP channels do not. The assay detects compounds blocking the cardiac rapid delayed-rectifier K channel and is an alternative to the classic "hERG test".Conclusion: hiPSC-CM are a useful in-vitro cardiac model in drug development since they respond appropriately to drugs that modify heart rate in humans.

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“…First, a mean residual betaxolol concentration of 0.4 6 0.2 ng/ml (excluding the patient on maintenance therapy with betaxolol) was present in plasma before the second drug application. Since the elimination phase half-life of betaxolol in plasma is about 12 to 16 hr in healthy adults (27,(31)(32)(33) and might rise up to 26 hr in elderly subjects (27), some accumulation of the drug during the dosing interval is expected to occur when maintenance treatment is started. In accordance with that, the patient on maintenance ocular treatment with betaxolol had a higher betaxolol concentration during the follow-up.…”

Section: Discussionmentioning

confidence: 99%

Plasma Concentration of Topically Applied Betaxolol in Elderly Glaucoma Patients

Vainio-Jylhä

Vuori

Pyykkö

et al. 2001

Journal of Ocular Pharmacology and Therapeutics

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Our aim was to study the concentration of betaxolol in plasma after its topical ocular use during the normal 12 hr dosing interval. Twenty microliters of betaxolol 0.5% solution were applied into both eyes of nine glaucoma patients, and the plasma concentrations of the drug were measured 12 hr thereafter using a radioreceptor assay. The same amount of betaxolol was then applied ocularly, and its concentration in plasma was measured at 5, 10, 15, 30 min and 1, 2, 4 and 8 hr thereafter. The mean (SD) concentration of betaxolol in plasma twelve hr after the first dose was 0.4 (0.2) ng/ml. After the second dose, the patients showed a biphasic concentration vs. time curve, the first peak occurring at 8 (4) min, and the second peak at 210 (132) min; the mean (SD) peak concentrations being 1.1 (0.3) and 2.0 (1.1) ng/ml, respectively. The area under the concentration vs. time curve showed a 4-fold variation among our patients. Topically applied betaxolol was rapidly absorbed into systemic circulation, and concentrations were detectable even at 12 hr. The interindividual variation in the systemic absorption of betaxolol was large.

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Beta‐adrenoceptor blocking effects and pharmacokinetics of betaxolol (SL 75212) in man.

Cited by 53 publications

References 19 publications

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

Multi-functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS)

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

Plasma Concentration of Topically Applied Betaxolol in Elderly Glaucoma Patients

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