Papers by Jan Willem van der Laan
Frontiers in toxicology, Apr 11, 2024
Experimental and Toxicologic Pathology, May 1, 2009
Toxicology Letters, Sep 1, 2022
Toxicology Letters, Sep 1, 2021
日本毒性学会学術年会 第41回日本毒性学会学術年会, 2014
Regulatory Toxicology and Pharmacology, Feb 1, 1997
cies findings, the target organs were the usual ones, such as lung and liver, or the tumors occur... more cies findings, the target organs were the usual ones, such as lung and liver, or the tumors occurred as a For the past 20-30 years, lifespan carcinogenicity result of an exaggerated pharmacodynamic action exstudies for pharmaceuticals have been required to be pected from the pharmacology of the compound. The carried out in two rodent species. Due to scientific results of the database thus question the need of mainprogress, the necessity/justification of lifespan studies taining the requirement of rodent carcinogenicity in two species for the assessment of carcinogenic risk studies in two species. ᭧ 1997 Academic Press of pharmaceuticals is currently under discussion. A study in one species (either rat or mouse) might suffice. To appraise the need for a study in a second species, a database was compiled of all pharmaceuticals INTRODUCTION tested for carcinogenicity for which a marketing authorization was applied for in Germany and The Netherlands since 1980. The incidence of treatment-related Until now, testing of pharmaceuticals for carcinotumor findings was determined in either rat or mouse genic potential has comprised lifespan studies in two or in both. Tumor findings occurred for nearly 50% of rodent species, usually the rat and the mouse (EEC, all compounds, with the rat being more sensitive than 1983). When this requirement was introduced, most the mouse. Specific attention was given to the question carcinogens known at that time were very potent and whether tumor findings in mice ever caused the regugenotoxic and, therefore, likely to cause tumors in more latory authorities to refuse registration, to restrict the than one species. It was hoped that cancer in humans proposed therapeutic indication of a pharmaceutical, could be reduced by detecting chemicals with carcinoor to apply a cautionary label. It was found that no genic potential and eliminating them from the environtumor findings in mice alone ever led to such a regulament. The request for long-term carcinogenicity studies tory action. In addition, whether mouse studies had in two rodent species was thus considered an approbeen important in interpreting the results of rat studpriate way to assess the carcinogenic risk for humans ies was determined. A negative mouse study (no turesulting from exposure to chemical compounds (Boormors found) was rarely used to declare the rat findings man et al., 1994). irrelevant to humans. A mechanistic explanation was Knowledge about mechanisms leading to carcinogeused as a much more important argument in the asnicity has vastly increased in the past decade. In a sessment of tumor findings in rats. In case of transspegrowing number of cases, additional mechanistic data were gathered to explain tumor responses. Several tu-1 The opinions expressed in this paper are strictly those of the morigenic mechanisms in rats and mice are now known authors and not necessarily those of the organizations they repreto be absent in humans (Alison et al., 1994), and this sent. casts doubt on the relevance of rodents as models for 2 To whom correspondence and reprint requests should be adcarcinogenesis in humans. At the same time, the batdressed at Preclinical Assessment Group of the Medicines Evaluation tery of short-term genotoxicity tests was extended. In-Board, Laboratory for Medicines and Medical Devices, National Institute for Public Health and the Environment, P.O. Box 1, 3720 BA, creasing mechanistic insight into the process of carci-Bilthoven, The Netherlands. nogenesis essential for the interpretation of these geno-3 Rapporteur on behalf of the Committee on Proprietary Medicinal toxicity tests provided much information that cannot Products for the ICH Carcinogenicity Topic.
Drug Information Journal, 2007
Drug Information Journal, 2002
A Guide to International Pharmaceutical Regulations, 2013
Aims The field of cell-based therapies for human diseases is currently evolving from promising tr... more Aims The field of cell-based therapies for human diseases is currently evolving from promising treatment options to established therapeutic concepts. The design of the non-clinical development program for cell-based products, intended to provide a rationale for treatment and to gain insight into the safety profile, is challenging because of limitations caused by speciesspecificity. The elements of the non-clinical package for cell-based products were evaluated using advice reports from the European Medicines Agency database from 2013-2018 to identify the approach followed for non-clinical development of these products. Methods The purpose of the in vivo studies was designated to be (a combination of) pharmacology/proof-of-concept, safety, biodistribution and/or tumourigenicity. For biodistribution and tumourigenicity also the need for, type and design of in vitro and in vivo studies were recorded. Results In vivo studies for cell-based therapies were primarily aimed at proof-ofconcept (75/86), followed by addressing safety (64/86), biodistribution (49/86) or tumourigenicity (46/86). No animal studies were performed or proposed by sponsors or regulators for six (out of 86) products, which contained cell types that have been studied in humans for a relatively long time. For one-third of the products in vivo biodistribution and/or tumourigenicity studies were not considered necessary. In vivo tumourigenicity studies were regarded of limited value. Conclusions Compared to more conventional medicinal products, the non-clinical development program for cell-based products was more tailored and focussing on proof-of-concept. For tumourigenicity an in vitro approach may suffice. Total omission of in vivo studies appears to be possible for products with sufficient clinical experience.
Brain Research, Sep 1, 1982
The role of the noradrenergi¢ system in quasi-morphine abstinence behaviour induced by din -propy... more The role of the noradrenergi¢ system in quasi-morphine abstinence behaviour induced by din -propylacetate (DPA) in rats has been studied. Depletion of noradrenaline (NA), by treatment with FLA-63, decreased the number of body shakes and the extent of horizontal activity evoked by DPA. Almost total suppression of these symptoms was obtained by injection of 20 ng morphine bilaterally into the locus coeruleus (LC). Destruction of the LC system by electrolytic lesion of the LC or by injection of 6-hydroxydopamine into the dorsal bundle revealed that degeneration of the NA system by at least 80~o appears to be necessary to decrease the number of body shakes. It is concluded that the noradrenerg, ic LC system fulfills a modulatory role in quasi-morphine abstinence behaviour induced by DPA.
British Journal of Clinical Pharmacology, Jun 2, 2023
PubMed, Nov 1, 1993
Benzodiazepines are known to decrease the dopamine turnover in the mesolimbic dopaminergic system... more Benzodiazepines are known to decrease the dopamine turnover in the mesolimbic dopaminergic system in stimulated rather than in basal conditions. Stimulation of dopamine turnover can be achieved by administration of the dopamine antagonist haloperidol. In the present paper, we tested the hypothesis that the effect of the benzodiazepines on the mesolimbic dopamine turnover is mediated by the benzodiazepine receptor, comparing the minimal potency of inhibition of the stimulated dopamine turnover with the ED50 values for the sedative and muscle-relaxant actions of the compounds. Five compounds were studied: desmethyldiazepam, lorazepam, flunitrazepam, triazolam and brotizolam. In contrast to the other compounds, lorazepam appeared to have no effect on the haloperidol-induced increase in DOPAC concentration. The relative potency of the benzodiazepines for this effect on the haloperidol-induced DOPAC increase is very different from that on sedation and muscle relaxation, suggesting that the effect on the mesolimbic dopamine turnover is not mediated by the classical benzodiazepine receptor. Since the background of this study was the relation between the dopaminergic effects and the development of psychotic symptoms during benzodiazepine withdrawal, this different pattern of the benzodiazepines is suggested to be an indication that benzodiazepines may differ qualitatively in the development of withdrawal symptoms after long-term treatment.
日本毒性学会学術年会 第43回日本毒性学会学術年会, 2016
European Neuropsychopharmacology, Dec 1, 1992
Withdrawal of benzodiazepines in man may induce hallucinatory symptoms and can evoke delusional d... more Withdrawal of benzodiazepines in man may induce hallucinatory symptoms and can evoke delusional depressions, which can be treated with dopamine-antagonistic drugs. Withdrawal of benzodiazepines in rats induces a strong hyperactivity during daytime, leaving the nighttime activity relatively undisturbed. This hyperactivity may be related to an enhanced dopaminergic activity in the mesolimbic area, especially in the nucleus accumbens. Mesolimbic dopaminergic activity may be specifically involved in the development of benzodiazepine withdrawal. Acute administration of benzodiazepines in otherwise non-treated rats, has been described not to affect the dopamine-turnover in the nucleus accumbens, measured by synthesis inhibition. However, activation by administration of haloperidol (feedback activation) can be suppressed by benzodiazepines effectively. Five different benzodiazepines viz. desmethyldiazepam (DMD), lorazepam (LRZ), brotizolam (BTZ), triazolam (TRZ) and flunitrazepam (FNZ) have been compared with respect to their acute effects. Using a 3-fold increase in dopamine turnover (determined by measuring the DOPAC-concentration), benzodiazepines were capable to reduce this increase maximally for 70-80% in the nucleus accumbens. The results point to a selective effect of benzodiazepines in the nucleus accumbens. The increase induced by haloperidol in the corpus striatum was found to be much less sensitive to benzodiazepines. In contrast to the other compounds lorazepam appeared to have no effect on haloperidol-induced increase in DOPAC concentration. Flunitrazepam and brotizolam did affect not only the haloperidol-induced DOPAC increase but also the basal DOPAC concentrations. Linear dose-response curves could not be obtained for the compounds, but minimal effective doses could be assessed. Flunitrazepam and triazolam appeared to be the most active compounds.(ABSTRACT TRUNCATED AT 250 WORDS)
PubMed, Sep 1, 1986
Administration of naloxone (0.5 mg/kg i.p.) to morphine-dependent rats induced a strong withdrawa... more Administration of naloxone (0.5 mg/kg i.p.) to morphine-dependent rats induced a strong withdrawal syndrome consisting of body shakes, escape jumping and various autonomic signs. Clonidine (750 micrograms/kg s.c.) had a dual action on naloxone-precipitated withdrawal symptoms in rats: a suppressive action on body shakes and a potentiating action on jumping. Both actions were found to be mediated by alpha 2-receptors which generally are responsible for sedative effects. Therefore, the action of alpha 2-agonists such as clonidine and azepexole was studied more extensively. Since both serotonergic and dopaminergic systems have been suggested to be involved in morphine-withdrawal jumping, the interaction of clonidine and azepexole with serotonergic and dopaminergic drugs was studied. Neither haloperidol (0.3 mg/kg i.p.) nor the benzamides sulpiride (40 mg/kg p.o.) and metoclopramide (8 mg/kg i.p.) affected the jumping potentiated by the alpha 2-agonists. However, the serotonin-agonist m-chlorophenylpiperazine (2.5 mg/kg i.p.) suppressed the effects of clonidine. Precipitation of jumping in morphine-dependent animals was more effective using bremazocine (1.0 mg/kg i.p.). This effect again could be potentiated by clonidine (750 micrograms/kg s.c.). A low dose of m-chlorophenylpiperazine (0.03 mg/kg i.p.) antagonized the clonidine-effect without affecting the basal jumping response. The data suggest that clonidine potentiates naloxone-precipitated jumping by decreasing serotonergic output while the administration of m-chlorophenylpiperazine can counteract this lack of serotonergic activity.
Psychopharmacology, May 1, 1984
Toxicology Letters, Oct 1, 2018
日本毒性学会学術年会 第41回日本毒性学会学術年会, 2014
Questions have been recently raised regarding the safety of vaccine adjuvants, particularly in re... more Questions have been recently raised regarding the safety of vaccine adjuvants, particularly in relation to autoimmunity or autoimmune disease(s)/disorder(s) (AID). The International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) formed a scientific committee and convened a 2-day workshop, consisting of technical experts from around the world representing academia, government regulatory agencies, and industry, to investigate and openly discuss the issues around adjuvant safety in vaccines. The types of adjuvants considered included oil-in-water emulsions and toll-like receptor (TLR) agonists. The state of science around the use of animal models and biomarkers for the evaluation and prediction of AID were also discussed. Following extensive literature reviews by the HESI committee, and presentations by experts at the workshop, several key points were identified, including the value of animal models used to study autoimmunity and AID toward studying novel vaccine adjuvants; whether there is scientific evidence indicating an intrinsic risk of autoimmunity and AID with adjuvants, or a higher risk resulting from the mechanism of action; and if there is compelling clinical data linking adjuvants and AID. The tripartite group of experts concluded that there is no compelling evidence supporting the association of vaccine adjuvants with autoimmunity signals. Additionally, it is recommended that future research on the potential effects of vaccine adjuvants on AID should consider carefully the experimental design in animal models particularly if they are to be used in any risk assessment, as an improper design and model could result in misleading information. Finally, studies on the mechanistic aspects and potential biomarkers related to adjuvants and autoimmunity phenomena could be developed.
日本毒性学会学術年会 第41回日本毒性学会学術年会, 2014
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Papers by Jan Willem van der Laan