Development of a Highly Cardioselective Ultra Short-Acting .BETA.-Blocker, ONO-1101.

Iguchi, Sadahiko; Iwamura, Hajime; Nishizaki, Minoru; Hayashi, Akio; Senokuchi, Kazuhiko; Kobayashi, Kaoru; Sakaki, Katsuhito; Hachiya, Katsutoshi; Ichioka, Yumiko; Kawamura, Masanori

doi:10.1248/cpb.40.1462

Cited by 179 publications

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“…7 Its beta 1 selectivity is greater than that of other beta blockers, such as esmolol (ß 1 /ß 2 = 33) and propranolol (ß 1 /ß 2 = 0.68). 7 Thus, the high cardioselectivity of landiolol may produce beneficial effects in some patients with bronchial asthma. Beta 2 adrenergic receptors exist on vascular smooth muscle and exert a vasodilating effect.…”

Section: Discussionmentioning

confidence: 96%

“…Landiolol has been developed as an ultrashort acting beta blocker, and has been reported to be nine times more potent than esmolol. 7 In addition to these properties, landiolol has highly selective beta 1 -adrenoceptor activity (beta 1 /beta 2 -receptor activity (ß 1 /ß 2 ) = 255) which studiedin vitrowith guinea pig right atria and trachea strips. 7 Its beta 1 selectivity is greater than that of other beta blockers, such as esmolol (ß 1 /ß 2 = 33) and propranolol (ß 1 /ß 2 = 0.68).…”

Section: Discussionmentioning

confidence: 99%

“…7 In addition to these properties, landiolol has highly selective beta 1 -adrenoceptor activity (beta 1 /beta 2 -receptor activity (ß 1 /ß 2 ) = 255) which studiedin vitrowith guinea pig right atria and trachea strips. 7 Its beta 1 selectivity is greater than that of other beta blockers, such as esmolol (ß 1 /ß 2 = 33) and propranolol (ß 1 /ß 2 = 0.68). 7 Thus, the high cardioselectivity of landiolol may produce beneficial effects in some patients with bronchial asthma.…”

Section: Discussionmentioning

confidence: 99%

“…phenylpropionate monohydrochloride}, has more potent cardiac properties than esmolol, 7 and has been developed for application in the emergency treatment of tachyarrhythmias in animals. [7][8][9] Theophylline toxicity induces severe tachyarrhythmias in humans [10][11][12] and in an animal model.…”

Section: Laboratory Investigationsmentioning

confidence: 99%

“…[7][8][9] Theophylline toxicity induces severe tachyarrhythmias in humans [10][11][12] and in an animal model. 13 The purpose of this study was to examine the effect of landiolol on hemodynamics during acute theophylline intoxication in halothane-anesthetized dogs.…”

Section: Laboratory Investigationsmentioning

confidence: 99%

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Modifications of the hemodynamic consequences of theophylline intoxication with landiolol in halothane-anesthetized dogs

Takahashi

Fujii

Hoshi

et al. 2000

Can J Anesth/J Can Anesth

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Purpose: To examine the effect of landiolol (ONO-1101), a new ultra-short acting, highly selective beta 1 blocker, on hemodynamic response to acute theophylline intoxication in anesthetized dogs.Methods: Thirty-four dogs were studied during halothane anesthesia. Aminophylline (50 mg·kg -1 over 20 min followed by infusion at 1.75 mg·kg -1 ·hr -1 ) was administered as a model of acute theophylline intoxication. Dogs were randomly enrolled into four landiolol groups (0, 1, 10, 100 µg·kg -1 ·min -1 ) to treat tachyarrhythmias. Hemodynamic variables, heart rate (HR), systemic blood pressure (SBP), pulmonary artery pressure, pulmonary artery occlusion pressure, and cardiac output (CO) were measured along with plasma concentrations of theophylline, epinephrine, and norepinephrine. Results: After 60 min, plasma concentration of theophylline reached 46.6 ± 4.0 (mean ± SD) µg·ml -1 , HR increased from 129 ± 21 to 193 ± 27 bpm (P < 0.0001) and CO increased from 1.6 ± 0.5 l·min -1 to 2.1 ± 0.4 l·min -1 (P < 0.0001), whereas SBP decreased from 139 ± 25 to 121 ± 25 mm Hg (P < 0.0001), with decreasing systemic vascular resistance. After intoxication, plasma epinephrine concentration increased from 125 ± 112 to 325 ± 239 pg·ml -1 (P < 0.0001), and norepinephrine concentration from 103 ± 61 to 133 ± 61 pg·ml -1 (P < 0.0011). Landiolol 10 µg·kg -1 ·min -1 decreased HR to pre-intoxication level, whereas HR returned to the intoxication baseline by 30 min after cessation of landiolol infusion. Conclusions: Landiolol controlled tachyarrhythmias associated with theophylline toxicity. The optimal effective dose of landiolol was 10 µg·kg -1 ·min -1 .Objectif : Examiner l'effet du landiolol (ONO-1101), nouveau bloqueur beta 1 hypersélectif à action ultrabrève, sur la réponse hémodynamique de l'intoxication aiguë à la théophylline chez des chiens anesthésiés. Méthode : L'étude a porté sur 34 chiens anesthésiés à l'halothane. L'aminophylline (50 mg·kg -1 pendant 20 min, suivi d'une perfusion à 1,75 mg·kg -1 ·hr -1 ) a été administrée pour provoquer l'intoxication aiguë à la théophylline. Les chiens, répartis au hasard en quatre groupes, ont reçu différentes doses de landiolol (0, 1, 10, 100 µg·kg -1 ·min -1 ) pour traiter la tachyarythmie. On a mesuré : la fréquence cardiaque (FC), la pression sanguine systémique (PSS), la pression artérielle pulmonaire, la pression artérielle pulmonaire bloquée et le débit cardiaque (DC) de même que les concentrations plasmatiques de théophylline, d'épinéphrine et de norépinéphrine. Résultats : Après 60 min, la concentration plasmatique de théophylline était de 46,6 ± 4,0 (moyenne ± écart type) µg·ml -1 , la FC avait augmenté de 129 ± 21 à 193 ± 27 bpm (P < 0,0001) et le DC était passée de 1,6 ± 0,5 l·min -1 à 2,1 ± 0,4 l·min -1 (P < 0,0001), tandis que la PSG avait baissé de 139 ± 25 à 121 ± 25 mm Hg (P < 0,0001) et que la résistance vasculaire générale diminuait. Après l'intoxication, la concentration plasmatique d'épinéphrine a augmenté de 125 ± 112 à 325 ± 239 pg·ml -1 (P < 0,0001), et la concentratio...

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Laboratory Investigationsmentioning

confidence: 99%

Section: Laboratory Investigationsmentioning

confidence: 99%

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Modifications of the hemodynamic consequences of theophylline intoxication with landiolol in halothane-anesthetized dogs

Takahashi

Fujii

Hoshi

et al. 2000

Can J Anesth/J Can Anesth

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Landiolol and Organ Failure in Patients With Septic Shock

Whitehouse,

Hossain,

Perkins

et al. 2023

JAMA

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ImportancePatients with septic shock undergo adrenergic stress, which affects cardiac, immune, inflammatory, and metabolic pathways. β-Blockade may attenuate the adverse effects of catecholamine exposure and has been associated with reduced mortality.ObjectivesTo assess the efficacy and safety of landiolol in patients with tachycardia and established septic shock requiring prolonged (&gt;24 hours) vasopressor support.Design, Setting, and ParticipantsAn open-label, multicenter, randomized trial involving 126 adults (≥18 years) with tachycardia (heart rate ≥95/min) and established septic shock treated for at least 24 hours with continuous norepinephrine (≥0.1 μg/kg/min) in 40 UK National Health Service intensive care units. The trial ran from April 2018 to December 2021, with early termination in December 2021 due to a signal of possible harm.InterventionSixty-three patients were randomized to receive standard care and 63 to receive landiolol infusion.Main Outcomes and MeasuresThe primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score from randomization through 14 days. Secondary outcomes included mortality at days 28 and 90 and the number of adverse events in each group.ResultsThe trial was stopped prematurely on the advice of the independent data monitoring committee because it was unlikely to demonstrate benefit and because of possible harm. Of a planned 340 participants, 126 (37%) were enrolled (mean age, 55.6 years [95% CI, 52.7 to 58.5 years]; 58.7% male). The mean (SD) SOFA score in the landiolol group was 8.8 (3.9) compared with 8.1 (3.2) in the standard care group (mean difference [MD], 0.75 [95% CI, −0.49 to 2.0]; P = .24). Mortality at day 28 after randomization in the landiolol group was 37.1% (23 of 62) and 25.4% (16 of 63) in the standard care group (absolute difference, 11.7% [95% CI, −4.4% to 27.8%]; P = .16). Mortality at day 90 after randomization was 43.5% (27 of 62) in the landiolol group and 28.6% (18 of 63) in the standard care group (absolute difference, 15% [95% CI, −1.7% to 31.6%]; P = .08). There were no differences in the number of patients having at least one adverse event.Conclusion and RelevanceAmong patients with septic shock with tachycardia and treated with norepinephrine for more than 24 hours, an infusion of landiolol did not reduce organ failure measured by the SOFA score over 14 days from randomization. These results do not support the use of landiolol for managing tachycardia among patients treated with norepinephrine for established septic shock.Trial RegistrationEU Clinical Trials Register Eudra CT: 2017-001785-14; isrctn.org Identifier: ISRCTN12600919

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Soft drug design: General principles and recent applications

2000

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Soft drug design represents a new approach aimed to design safer drugs with an increased therapeutic index by integrating metabolism considerations into the drug design process. Soft drugs are new therapeutic agents that undergo predictable metabolism to inactive metabolites after exerting their therapeutic effect. Hence, they are obtained by building into the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified. In an attempt to systematize and summarize the related work done in a number of laboratories, including ours, the present review presents an overview of the general soft drug design principles and provides a variety of specific examples to illustrate the concepts. A number of already marketed drugs, such as esmolol, remifentanil, or loteprednol etabonate, resulted from the successful application of such design principles. Many other promising drug candidates are currently under investigation in a variety of fields including possible soft antimicrobials, anticholinergics, corticosteroids, β‐blockers, analgetics, ACE inhibitors, antiarrhythmics, and others. Whenever possible, pharmacokinetic and pharmacodynamic properties are briefly summarized and compared to those of other compounds used in the same field. © 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 1, 58–101, 2000.

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Development of a Highly Cardioselective Ultra Short-Acting .BETA.-Blocker, ONO-1101.

Cited by 179 publications

References 1 publication

Modifications of the hemodynamic consequences of theophylline intoxication with landiolol in halothane-anesthetized dogs

Modifications of the hemodynamic consequences of theophylline intoxication with landiolol in halothane-anesthetized dogs

Landiolol and Organ Failure in Patients With Septic Shock

Soft drug design: General principles and recent applications

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