Wolfgang Stengel | Hochschule für Technik und Wirtschaft, HTW Berlin (original) (raw)

Papers by Wolfgang Stengel

ALTEX, 2011

european Coalition to end Animal experiments (eCeAe), london, UK 1 Introduction the Cosmetics Dir... more european Coalition to end Animal experiments (eCeAe), london, UK 1 Introduction the Cosmetics Directive (Directive 76/768/eeC), now recast as Regulation 1223/2009, bans testing on animals for cosmetic purposes as of March 2009. In addition the "marketing" (i.e. import and sale) of products and ingredients tested on animals outside europe also is prohibited after that date. A postponement of the marketing ban until 2013 was provided for three endpoints however-toxicokinetics, repeated dose, and reproductive toxicity. At the time, these tests were considered harder to replace. Under the terms of the Cosmetics Directive, the european Commission shall publish a proposal for an extension of this deadline if it decides that alternatives for these three tests will not be available by this date. As part of this process, the Commission gathered experts from across europe in May 2010 to produce a report on the status of alternatives for cosmetics testing. the aim of the experts' report was to evaluate whether alternatives would be available by 2013 and, if not, to establish recommendations and a timeline for complete replacement. In July 2010, a draft version of the report was made available for public comment, comprising five chapters covering five endpoints: repeated dose, skin sensitization, carcinogenicity, toxicokinetics, and reproductive toxicity (http://ec.europa.eu/consumers/sectors/cosmetics/documents/public_consultation/index_en.htm). the reports covered how information on the endpoint is currently derived, (i.e. Scientific Committee on Consumer Safety (SCCS) requirements for in vivo tests) and then summarized the various alternative approaches, including in vitro methods, QSARs (Quantitative Structure Activity Relationships), and Summary The 7 th Amendment to the EU's Cosmetic Directive (now recast as Regulation 1223/2009) bans the testing of cosmetic ingredients and products on animals, effective 2009. An extension until 2013 was granted, for marketing purposes only, for three endpoints: repeated dose, toxicokinetics, and reproductive toxicity. If the European Commission determines that alternatives for these endpoints are not likely to be available, it can propose a further extension. To this end, the Commission has instructed experts to produce reports on the status of alternatives for the 2013 deadline. We criticized the draft reports on a number of issues. First, the experts fell into the "high fidelity fallacy trap," i.e. asserting that full replication of the in vivo response, as opposed to high predictivity, is required before an animal test can be considered useful for regulatory purposes. Second, the experts' reports were incomplete, omitting various methods and failing to provide data on the validity, reliability, and applicability of all the methods discussed, regardless of whether the methods were in vivo, in vitro, or in silico. In this paper we provide a summary of our criticisms and provide some of the missing data in an alternative proposal for replacement of animal tests by 2013. It is our belief that use of the Threshold of Toxicological Concern (TTC) will be a useful method to mitigate much animal testing. Alternative approaches for carcinogenicity and skin sensitization could be considered sufficient in the very near future, even though these tests are not listed under the 2013 extension. For repeated dose, toxicokinetics, and reproductive toxicity a combination of in vitro methods may be able to provide appropriate protection for consumers, especially when viewed in the context of the poor predictivity of the animal models they replace. We hope the revised report will incorporate these comments, since a more thorough and positive review is required if the elimination of animal testing for cosmetics in Europe and beyond is to be achieved.

European Journal of Pharmacology, 1998

Evidence has accumulated that classic L-type Ca 2q channel blockers with a dihydropyridine struct... more Evidence has accumulated that classic L-type Ca 2q channel blockers with a dihydropyridine structure also inhibit T-type Ca 2q channels in certain types of central and peripheral neurons and in smooth muscle cells, albeit with a lower potency. Thus beneficial therapeutic effects of dihydropyridines in cardiovascular and neurological diseases may not only be associated with L-type but also with T-type Ca 2q channel blockade. Little is known about the exact order of potency of dihydropyridine derivatives at T-type Ca 2q channels. Here we investigate the efficacy and potency of four therapeutically used compounds, i.e. nifedipine, nimodipine, nicardipine, niguldipine, in the neuroblastoma-glioma cell line NG108-15. For comparative purposes the Ca 2q channel agonist Bay K 8644 was included. Ca 2q channel currents were measured with the whole-cell voltage clamp technique. Subtype Ca 2q channel currents were separated by clamp protocol and selective blockers. T-type Ca 2q channel currents were inhibited with decreasing potency in the order Ž. 2q niguldipine) nicardipine) nimodipine) nifedipine IC-values 244 nM, 2.5 mM, 9.8 mM, 39 mM , whereas L-type Ca channel 50 Ž. 2q currents were blocked with similar potency IC for nicardipine 75 nM. Bay K 8644 increased T-type Ca channel current at 50 Ž. 2q nanomolar concentrations i.e. 95 " 16% increase by 300 nM. T-type Ca channel block was completely reversible with exception of the block by niguldipine. Our results indicate a variability of two orders of magnitude in potency of T-type Ca 2q channel block by the dihydropyridine derivatives investigated. It is speculated that the relation between the Land T-type Ca 2q channel block may determine the therapeutic profile of a dihydropyridine derivative. q 1998 Elsevier Science B.V.

ALTEX, 2011

european Coalition to end Animal experiments (eCeAe), london, UK 1 Introduction the Cosmetics Dir... more european Coalition to end Animal experiments (eCeAe), london, UK 1 Introduction the Cosmetics Directive (Directive 76/768/eeC), now recast as Regulation 1223/2009, bans testing on animals for cosmetic purposes as of March 2009. In addition the "marketing" (i.e. import and sale) of products and ingredients tested on animals outside europe also is prohibited after that date. A postponement of the marketing ban until 2013 was provided for three endpoints however-toxicokinetics, repeated dose, and reproductive toxicity. At the time, these tests were considered harder to replace. Under the terms of the Cosmetics Directive, the european Commission shall publish a proposal for an extension of this deadline if it decides that alternatives for these three tests will not be available by this date. As part of this process, the Commission gathered experts from across europe in May 2010 to produce a report on the status of alternatives for cosmetics testing. the aim of the experts' report was to evaluate whether alternatives would be available by 2013 and, if not, to establish recommendations and a timeline for complete replacement. In July 2010, a draft version of the report was made available for public comment, comprising five chapters covering five endpoints: repeated dose, skin sensitization, carcinogenicity, toxicokinetics, and reproductive toxicity (http://ec.europa.eu/consumers/sectors/cosmetics/documents/public_consultation/index_en.htm). the reports covered how information on the endpoint is currently derived, (i.e. Scientific Committee on Consumer Safety (SCCS) requirements for in vivo tests) and then summarized the various alternative approaches, including in vitro methods, QSARs (Quantitative Structure Activity Relationships), and Summary The 7 th Amendment to the EU's Cosmetic Directive (now recast as Regulation 1223/2009) bans the testing of cosmetic ingredients and products on animals, effective 2009. An extension until 2013 was granted, for marketing purposes only, for three endpoints: repeated dose, toxicokinetics, and reproductive toxicity. If the European Commission determines that alternatives for these endpoints are not likely to be available, it can propose a further extension. To this end, the Commission has instructed experts to produce reports on the status of alternatives for the 2013 deadline. We criticized the draft reports on a number of issues. First, the experts fell into the "high fidelity fallacy trap," i.e. asserting that full replication of the in vivo response, as opposed to high predictivity, is required before an animal test can be considered useful for regulatory purposes. Second, the experts' reports were incomplete, omitting various methods and failing to provide data on the validity, reliability, and applicability of all the methods discussed, regardless of whether the methods were in vivo, in vitro, or in silico. In this paper we provide a summary of our criticisms and provide some of the missing data in an alternative proposal for replacement of animal tests by 2013. It is our belief that use of the Threshold of Toxicological Concern (TTC) will be a useful method to mitigate much animal testing. Alternative approaches for carcinogenicity and skin sensitization could be considered sufficient in the very near future, even though these tests are not listed under the 2013 extension. For repeated dose, toxicokinetics, and reproductive toxicity a combination of in vitro methods may be able to provide appropriate protection for consumers, especially when viewed in the context of the poor predictivity of the animal models they replace. We hope the revised report will incorporate these comments, since a more thorough and positive review is required if the elimination of animal testing for cosmetics in Europe and beyond is to be achieved.

European Journal of Pharmacology, 1998

Evidence has accumulated that classic L-type Ca 2q channel blockers with a dihydropyridine struct... more Evidence has accumulated that classic L-type Ca 2q channel blockers with a dihydropyridine structure also inhibit T-type Ca 2q channels in certain types of central and peripheral neurons and in smooth muscle cells, albeit with a lower potency. Thus beneficial therapeutic effects of dihydropyridines in cardiovascular and neurological diseases may not only be associated with L-type but also with T-type Ca 2q channel blockade. Little is known about the exact order of potency of dihydropyridine derivatives at T-type Ca 2q channels. Here we investigate the efficacy and potency of four therapeutically used compounds, i.e. nifedipine, nimodipine, nicardipine, niguldipine, in the neuroblastoma-glioma cell line NG108-15. For comparative purposes the Ca 2q channel agonist Bay K 8644 was included. Ca 2q channel currents were measured with the whole-cell voltage clamp technique. Subtype Ca 2q channel currents were separated by clamp protocol and selective blockers. T-type Ca 2q channel currents were inhibited with decreasing potency in the order Ž. 2q niguldipine) nicardipine) nimodipine) nifedipine IC-values 244 nM, 2.5 mM, 9.8 mM, 39 mM , whereas L-type Ca channel 50 Ž. 2q currents were blocked with similar potency IC for nicardipine 75 nM. Bay K 8644 increased T-type Ca channel current at 50 Ž. 2q nanomolar concentrations i.e. 95 " 16% increase by 300 nM. T-type Ca channel block was completely reversible with exception of the block by niguldipine. Our results indicate a variability of two orders of magnitude in potency of T-type Ca 2q channel block by the dihydropyridine derivatives investigated. It is speculated that the relation between the Land T-type Ca 2q channel block may determine the therapeutic profile of a dihydropyridine derivative. q 1998 Elsevier Science B.V.