Validation of respiratory safety pharmacology models: Conscious and anesthetized beagle dogs

Authier, Simon; Legaspi, Margarita; Gauvin, Dominique; Chaurand, Fernando; Fournier, Sébastien; Troncy, Éric

doi:10.1016/j.vascn.2007.08.001

Cited by 22 publications

(5 citation statements)

References 42 publications

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“…In other words, does the chosen model accurately identify the safety liability of the drug candidate? Validation of Safety Pharmacology test systems for GLP compliance is achieved at each test site using positive control drugs with currently accepted models ( Hauser et al ., 2005 ; Chaves et al ., 2006 , 2007 ; Authier et al ., 2007 , 2008 ). At a higher level, some initiatives such as the QT‐PRODACT project have helped characterize the sensitivity of the methodologies and inter‐facility variability ( Ando et al ., 2005 ; Miyazaki et al ., 2005 ; Omata et al ., 2005 ; Sasaki et al ., 2005 ; Tashibu et al ., 2005 ; Toyoshima et al ., 2005 ).…”

Section: The Development Validation and Accreditation Of Preclinicalmentioning

confidence: 99%

Principles of Safety Pharmacology

Pugsley

Authier

Curtis

2008

British J Pharmacology

212

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Safety Pharmacology is a rapidly developing discipline that uses the basic principles of pharmacology in a regulatory-driven process to generate data to inform risk/benefit assessment. The aim of Safety Pharmacology is to characterize the pharmacodynamic/pharmacokinetic (PK/PD) relationship of a drug's adverse effects using continuously evolving methodology. Unlike toxicology, Safety Pharmacology includes within its remit a regulatory requirement to predict the risk of rare lethal events. This gives Safety Pharmacology its unique character. The key issues for Safety Pharmacology are detection of an adverse effect liability, projection of the data into safety margin calculation and finally clinical safety monitoring. This article sets out to explain the drivers for Safety Pharmacology so that the wider pharmacology community is better placed to understand the discipline. It concludes with a summary of principles that may help inform future resolution of unmet needs (especially establishing model validation for accurate risk assessment). Subsequent articles in this issue of the journal address specific aspects of Safety Pharmacology to explore the issues of model choice, the burden of proof and to highlight areas of intensive activity (such as testing for drug-induced rare event liability, and the challenge of testing the safety of so-called biologics (antibodies, gene therapy and so on.).

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Section: The Development Validation and Accreditation Of Preclinicalmentioning

confidence: 99%

Principles of Safety Pharmacology

Pugsley

Authier

Curtis

2008

British J Pharmacology

212

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“…One possible reason for the elevated haematocrit is splenic contraction, mediated by release of catecholamines during apnoea and/or hypoxaemia. Splenic contraction leads to an increase of between 15% and 60% in circulating red blood cells (Authier et al. 2008).…”

Section: Discussionmentioning

confidence: 99%

Medetomidine/midazolam/ketamine anaesthesia in ferrets: effects on cardiorespiratory parameters and evaluation of plasma drug concentrations

Schernthaner¹,

Lendl²,

Hartmann

et al. 2011

Veterinary Anaesthesia and Analgesia

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“…Стандартные оцениваемые показатели включают частоту дыхания, дыхательный объем, минутную вентиляцию, газы крови. Кроме того, при использовании анестезии могут быть вживлены датчики плеврального давления, позволяющие оценивать такие параметры, как сопротивление и эластичность легкого [22].…”

Section: дыхательная системаunclassified

“…Действительно, в исследовании на собаках, в котором было проведено сравнение параметров, полученных на наркотизированных и бодрствующих животных, показана большая чувствительность модели в том случае, когда животные находились в сознании по сравнению с состоянием под наркозом. Так, сравнение газов артериальной крови и значений pH, зарегистрированных через 5 мин после введения физиологического раствора у наркотизированных и бодрствующих собак, ясно показало угнетение дыхания, вызванное анестезией пропофолом [22].…”

Section: дыхательная системаunclassified

Dogs in preclinical research

Makarova,

Makarov

2023

Lab Anim Sci Rus

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According to local and international regulatory documents, in addition to rodent second non-rodent species are required to provide sufficient toxicological data. The most commonly the Beagle dog is used as the second non-rodent species. The wide use of Beagle dogs has become possible due to a number of advantages of this breed: medium size, balanced temperament, friendliness, relative ease of handling. Recently, the use of dogs in preclinical studies has been declining for humanitarian reasons. If there is no alternative to the use of dogs, every effort must be made to implement the principles of the 3Rs in experimental practice. Reducing the number of animals in the experiment can be achieved through the use of combined experimental designs, when additional parameters (safety pharmacology, immunotoxicity, reproductive toxicity, pharmacokinetic) are included in the main toxicological study. Long-term toxicity studies (9 months) are required for drugs with planned long-term clinical use, while shorter studies (3 months, 6 months) may be needed to support the first phases of clinical studies. Instead of conducting several toxicity studies, one long-term study may be considered, without interim euthanasia (3 or 6 months of drug administration), but at these points the biomarkers are evaluated, the range of which is similar to those evaluated in clinical studies. During the long-term use of Beagles in biomedical research, data on the physiology, biochemistry, and morphology of this breed have been accumulated. The use of the available literature data as well as the available laboratory historical data also makes it possible to reduce the number of animals in the experiment, for example by reducing the number of animals in the control groups and in the recovery groups. Preliminary analysis of the available scientific data on the test compound or on analogous compounds may lead to the reduction of animals in the experiment without compromising the clinical safety. In addition, due to the scientifically based approach and careful design of the experiment, euthanasia of all animals in the experiment can be avoided. Laboratory dogs are often rehomed nowadays into private households after their use in research.

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Validation of respiratory safety pharmacology models: Conscious and anesthetized beagle dogs

Cited by 22 publications

References 42 publications

Principles of Safety Pharmacology

Principles of Safety Pharmacology

Medetomidine/midazolam/ketamine anaesthesia in ferrets: effects on cardiorespiratory parameters and evaluation of plasma drug concentrations

Dogs in preclinical research

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