Use of the whole-embryo culture system in drug safety assessment?

Bechter, R.; Schön, Hans

doi:10.1016/0887-2333(88)90008-2

Cited by 16 publications

(8 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is a high rate of concurrence between in vivo and in vitro embryotoxicity of several compounds [91]. In the case of non-correlation, an additional pharmacokinetic analysis comparing the embryo concentration of the test substance in vivo and in vitro may explain the lack of concurrence.…”

Section: Pharmacokinetic Aspects In Wecmentioning

confidence: 99%

Whole Embryo Culture: An Important Tool in Developmental Toxicology Today

Flick

Klug²

2006

CPD

View full text Add to dashboard Cite

The number of candidate chemicals or drugs for registration and authorization is increasing at a fast rate and only few of the existing substances have been tested for teratogenicity to date. Therefore, there is high pressure on authorities to accept models like the whole embryo culture as a screening system for safety evaluation procedures. In view of this background the gradual development of the whole embryo culture into a standardized, scientifically validated tool for developmental toxicology during the last 70 years is summarized. The methodological development of the culture technique is described with the completion, improvement and refinement of the basic culture method as main intention. Special attention was paid to different culture techniques, culture media, gassing schedules, and evaluation strategies. Furthermore the importance of taking "in vitro pharmacokinetics" into consideration when a comparison of in vitro/in vivo results from embryotoxicity testing is intended, is stressed. Additionally, the demonstration of the broad spectrum of useful scientific applications when using this culture system in combination with sophisticated analytical techniques is demonstrated. Finally, an overview on different strategies for the validation of this culture system as an in vitro embryo toxicity test is provided and the officially accepted formal validation process for this application is summarized. The successful validation makes the whole embryo culture a complex in vitro embryotoxicity test with high accuracy and predictability. This robust in vitro system modelling the main phase of rodent organogenesis with a high reproducibility is valuable enough to attract special attention in related scientific fields.

show abstract

Section: Pharmacokinetic Aspects In Wecmentioning

confidence: 99%

Whole Embryo Culture: An Important Tool in Developmental Toxicology Today

Flick

Klug²

2006

CPD

View full text Add to dashboard Cite

show abstract

“…When the artificial in vitro exposure conditions are combined with the relatively brief period during which embryos can be cultured and the resultant abbreviated time for regulation, the likelihood of observing developmental delays in cultured embryos is enhanced. In fact, several review papers on whole embryo culture [Bechter and Schön, 1988;Tesh, 1988;New, 1990;Guest et al, 1994] have noted that, even among embryos cultured under control conditions, NTDs are regularly observed at incidence rates of 2-7%, although rates can be as low as 0% and as high as 10+%. These rates greatly exceed the incidences of malformations seen at term in rodents (Table II) and in humans (Table I).…”

Section: Embryo Culture Studiesmentioning

confidence: 99%

Apparent lability of neural tube closure in laboratory animals and humans

1999

View full text Add to dashboard Cite

Neural tube defects (NTDs), a set of structural abnormalities affecting the brain, spinal cord, and the skeletal and connective tissues that protect them, are common malformations among humans and laboratory animals. The embryogenesis of the neural tube is presented to convey the complexity of the phenomenon, the multiplicity of requisite cellular and subcellular processes, and the precise timing of events that must occur for successful neural tube development. Interruption, even transitory, of any of these intricate processes or disruption of an embryo's developmental schedule can lead to an NTD. The population distribution of human NTDs demonstrates that genetic predisposition functions in susceptibility to NTDs. Data from animal studies support these concepts. NTDs are common outcomes in developmental toxicity safety assessments, occurring among control and treated groups. Numerous agents have caused increased levels of NTDs in laboratory animals, and species with shorter gestational periods appear more prone to toxicant-induced NTDs than those with longer gestations. Data from post-implantation whole embryo culture, although not predictive of human risk, are useful in studying neurulation mechanisms and in demonstrating the importance of maintaining embryonic schedules of development. We conclude that the concept that NTDs are produced by only a few toxicants that selectively target the developing nervous system is untenable. Rather, the combination of the time in gestation that an agent is applied, its dose, and its ability to disrupt critical processes in neurulation leads to NTDs. We further conclude that, because of both the relatively high prevalence and the multifactorial nature of NTDs, the mere occurrence of an NTD is insufficient for inferring that the defect was caused by an exogenous agent.

show abstract

“…The clinical significance of a specific drug-drug interaction depends on the degree of accumulation of the substrate and the therapeutic window of the substrate (Bachmann, Lewis, 2005). The combination of theophylline and ketotifen is often used in respiratory tract infections and some have suggested that the combination is effective (Benjamin et al, 1994), while others have postulated that the combination may be embryotoxic, leading to growth retardation and morphological abnormalities (Bechter, Schön, 1988). The major goal of the present study was to elucidate the possible importance of drug-drug interactions (DDIs) as a contributing factor towards drug safety and finally to observe and determine the stability of the complexes which could be formed by the interaction of ketotifen fumarate with anhydrous theophylline in aqueous media at variable pH.…”

Section: Introductionmentioning

confidence: 99%

In vitro study on the interaction of ketotifen fumarate with anhydrous theophylline

Sayeed

Habib

Rahman

et al. 2012

Braz. J. Pharm. Sci.

View full text Add to dashboard Cite

The purpose of the present study was to investigate the interaction between ketotifen fumarate and anhydrous theophylline in aqueous media of various pH (1.2 and 6.8). Using Job's continuous-variation analysis and Ardon's spectrophotomeric measurement methods, the values of the stability constants of theophylline with ketotifen were determined at a fixed temperature (37 o C) at various pH. The stability constants, ranging between 5.66 and 9.92, were derived from Ardon's plot, indicating that comparatively stable complexes had formed as a result of an interaction between the drugs. However, following the interaction of theophylline with ketotifen, stability constants were <1 at gastric pH (1.2) and intestinal pH (6.8). Concurrent administration of ketotifen and theophylline could result in the formation of a stable complex and this is likely to reduce the therapeutic activities of both drugs.Uniterms: Stability constant. Job's method. Ardon's method. Ketotifen. Theophylline.O objetivo do presente estudo foi investigar a interação entre o fumarato de cetotifeno e a teofilina anidra em meios aquosos com vários pH (1,2 e 6,8). Utilizando a análise da variação contínua de Job e os métodos de medida espectrofotométrica de Ardon, os valores das constantes de estabilidade da teofilina com o cetotifeno foram determinados em temperatura fixa (37 oC) em vários pH. As constantes de estabilidade, variando entre 5,66 e 9,92 derivaram-se a partir do delineamento de Ardon, indicando, comparativamente, que complexos estáveis se formaram como resultado da interação entre os fármacos. Entretanto, seguindo a interação da teofilina com o cetotifeno, as constantes de estabilidade foram <1, em pH gástrico (1,2) e intestinal (8,8). A administração concomitante de cetotifeno e teofilina poderia resultar na formação de complexo estável, o que reduz a atividade terapêutica de ambos os fármacos. Uniterms: Constante de estabilidade. Método de Job. Método de Ardon. Cetotifeno. Teofilina.

show abstract

Use of the whole-embryo culture system in drug safety assessment?

Cited by 16 publications

References 15 publications

Whole Embryo Culture: An Important Tool in Developmental Toxicology Today

Whole Embryo Culture: An Important Tool in Developmental Toxicology Today

Apparent lability of neural tube closure in laboratory animals and humans

In vitro study on the interaction of ketotifen fumarate with anhydrous theophylline

Contact Info

Product

Resources

About