Bueters TJ


Full name : Bueters Tjerk JH

First name : Tjerk JH

Mail : TNO Defence\; Security and Safety\; BU CBRN Protection\; PO Box 45\; Lange Kleiweg 137, Rijswijk, 2288

Zip Code : 2280 AA

City : Rijswijk

Country : The Netherlands

Email : Bueters@pml.tno.nl

Phone : +31 (0)15 284 3334

Fax : +31 (0)15 284 3963

Website :

Directory :

References (8)

Title : Cardiovascular effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) decisive for its therapeutic efficacy in sarin poisoning - Joosen_2004_Arch.Toxicol_78_34
Author(s) : Joosen MJ , Bueters TJ , van Helden HP
Ref : Archives of Toxicology , 78 :34 , 2004
Abstract : Mortality and occurrence of cholinergic symptoms upon sarin intoxication (144 micro g/kg s.c., approximately 2 x LD50) in rats is completely prevented by treatment with the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA, 2 mg/kg i.m.). Previously, we have shown that CPA treatment altered the distribution of sarin into the brain, presumably through its cardiovascular side effects. Therefore, the objective of the present study was to evaluate the contribution of the cardiodepressant effects of CPA to its therapeutic efficacy against sarin intoxication. Intramuscular treatment of rats with 0.5 and 2.0 mg/kg CPA 1 min after sarin poisoning attenuated most cholinergic symptoms and prevented mortality, which seemed to be directly associated with an immediate strong and long-lasting bradycardia and hypotension caused by CPA. Treatment with lower doses of CPA (0.1 and 0.05 mg/kg i.m.) caused similar levels of bradycardia and hypotension, albeit a few minutes later than at the higher doses of CPA. Upon sarin intoxication, this was correlated with increased incidence of cholinergic symptoms and decreased survival rates. Pretreatment with the peripheral adenosine A1 receptor antagonist 8- p-sulphophenyltheophylline (8-PST, 20 mg/kg i.p.) counteracted the cardiodepressant effects of 0.05 mg/kg CPA almost completely, thereby nearly abolishing its therapeutic efficacy against sarin poisoning. In conclusion, the present results strongly indicate that bradycardia and hypotension induced by the peripheral adenosine A1 receptor play a prominent role in the therapeutic efficacy of CPA in cases of sarin poisoning.
ESTHER : Joosen_2004_Arch.Toxicol_78_34
PubMedSearch : Joosen_2004_Arch.Toxicol_78_34
PubMedID: 14508639

Title : Block of neuronal nicotinic acetylcholine receptors by organophosphate insecticides - Smulders_2004_Toxicol.Sci_82_545
Author(s) : Smulders CJ , Bueters TJ , Vailati S , van Kleef RG , Vijverberg HP
Ref : Toxicol Sci , 82 :545 , 2004
Abstract : Chronic and acute exposure to organophosphate (OP) pesticides may lead to persistent neurological and neurobehavioral effects, which cannot be explained by acetylcholinesterase (AChE) inhibition alone. It is suggested that other brain proteins are involved. Effects of commonly used organophosphate pesticides on rat neuronal alpha4beta2 nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes have been investigated using the two-electrode voltage clamp technique. Several OP pesticides, e.g., parathion-ethyl, chlorpyrifos and disulfoton, inhibited the ACh-induced ion current with potencies in the micromolar range. The potency of inhibition increased with increasing concentrations of the agonist ACh. Comparison of the potency of nAChR inhibition with the potency of AChE inhibition demonstrated that some OPs inhibit nAChRs more potently than AChE. Binding experiments on alpha4beta2 nAChRs showed that the OPs noncompetitively interact with nAChRs. The inhibitory effects on nAChRs are adequately described and explained by a sequential two-step mechanism, in which rapidly reversible OP binding to a separate binding site leads to inhibition followed by a stabilization of the blocked state or receptor desensitization. It is concluded that OPs interact directly with neuronal alpha4beta2 nAChRs to inhibit the agonist-induced response. This implicates that neuronal alpha4beta2 nAChRs are additional targets for some OP pesticides.
ESTHER : Smulders_2004_Toxicol.Sci_82_545
PubMedSearch : Smulders_2004_Toxicol.Sci_82_545
PubMedID: 15342957

Title : Effects of carbamate insecticides on rat neuronal alpha4beta4 nicotinic receptors and rat brain acetylcholinesterase. -
Author(s) : Smulders C , Bueters TJ , van Kleef RG , Vijverberg HP
Ref : Cholinergic Mechanisms, CRC Press :715 , 2004

Title : Therapeutic efficacy in organophosphate poisoning by inhibiting central release of acetylcholine. -
Author(s) : Bueters TJ , Groen B , Harrison PK , Tattersall JE , Ijzerman AP , Danhof M , van Helden HP
Ref : Cholinergic Mechanisms, CRC Press :255 , 2004

Title : Adenosine A1 receptor agonist N6-cyclopentyladenosine affects the inactivation of acetylcholinesterase in blood and brain by sarin - Bueters_2003_J.Pharmacol.Exp.Ther_304_1307
Author(s) : Bueters TJ , Joosen MJ , van Helden HP , Ijzerman AP , Danhof M
Ref : Journal of Pharmacology & Experimental Therapeutics , 304 :1307 , 2003
Abstract : The objective of the present study was to develop a kinetics of pharmacodynamics model to properly describe and investigate the in vivo interaction between the selective adenosine A(1) agonist N(6)-cyclopentyladenosine (CPA), acetylcholinesterase (AChE) in blood and brain, and the AChE-inhibitor sarin (isopropylmethylphosphonofluoridate). The direct interaction of CPA (2 microM) on the inhibition of AChE by sarin was studied in vitro in heparinized rat blood and in 10% (w/v) brain homogenate. CPA did not directly influence the sarin-mediated inactivation of AChE in either system. In sarin-poisoned (144 microg/kg s.c.) rats not treated with CPA, AChE was completely inactivated in blood and brain within 7 min. CPA (2 mg/kg i.m.) treatment, 1 min after sarin administration, caused a small delay in the inhibition of AChE in blood. Treatment with CPA, 2 min before sarin, protected the neuronal AChE partially from being inhibited, but not the enzyme localized in blood. With a dose-response-time model the proportion of the dose of sarin reaching the site of action was estimated to be 48 +/- 12 or 13 +/- 3% after CPA post- or pretreatment, respectively. A correlation between the residual AChE activity in the brain and the incidence of cholinergic symptoms could be established with logistic regression analysis: lower inhibition of AChE in the brain precluded the onset of critical symptoms. In conclusion, CPA affects the concentration of sarin reaching the site of action, which contributes to the protection previously observed in sarin-poisoned rats.
ESTHER : Bueters_2003_J.Pharmacol.Exp.Ther_304_1307
PubMedSearch : Bueters_2003_J.Pharmacol.Exp.Ther_304_1307
PubMedID: 12604711

Title : Selective effects of carbamate pesticides on rat neuronal nicotinic acetylcholine receptors and rat brain acetylcholinesterase - Smulders_2003_Toxicol.Appl.Pharmacol_193_139
Author(s) : Smulders CJ , Bueters TJ , van Kleef RG , Vijverberg HP
Ref : Toxicol Appl Pharmacol , 193 :139 , 2003
Abstract : Effects of commonly used carbamate pesticides on rat neuronal nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes have been investigated using the two-electrode voltage clamp technique. The potencies of these effects have been compared to the potencies of the carbamates to inhibit rat brain acetylcholinesterase. The potency order of six carbamates to inhibit alpha4beta4 nicotinic receptors is fenoxycarb > EPTC > carbaryl, bendiocarb > propoxur > aldicarb with IC50 values ranging from 3 microM for fenoxycarb to 165 microM for propoxur and >1 mM for aldicarb. Conversely, the potency order of these carbamates to inhibit rat brain acetylcholinesterase is bendiocarb > propoxur, aldicarb > carbaryl > EPTC, fenoxycarb with IC50 values ranging from 1 microM for bendiocarb to 17 microM for carbaryl and > mM for EPTC and fenoxycarb. The alpha4beta2, alpha3beta4, and alpha3beta2 nicotinic acetylcholine receptors are inhibited by fenoxycarb, EPTC, and carbaryl with potency orders similar to that for alpha4beta4 receptors. Comparing the potencies of inhibition of the distinct subtypes of nicotinic acetylcholine receptors shows that the alpha3beta2 receptor is less sensitive to inhibition by fenoxycarb and EPTC. The potency of inhibition depends on the carbamate as well as on a combination of alpha and beta subunit properties. It is concluded that carbamate pesticides affect different subtypes of neuronal nicotinic receptors independently of acetylcholinesterase inhibition. This implicates that neuronal nicotinic receptors are additional targets for some carbamate pesticides and that these receptors may contribute to carbamate pesticide toxicology, especially after long-term exposure.
ESTHER : Smulders_2003_Toxicol.Appl.Pharmacol_193_139
PubMedSearch : Smulders_2003_Toxicol.Appl.Pharmacol_193_139
PubMedID: 14644616

Title : Partial adenosine A(1) receptor agonists inhibit sarin-induced epileptiform activity in the hippocampal slice - Harrison_2003_Eur.J.Pharmacol_471_97
Author(s) : Harrison PK , Bueters TJ , Ijzerman AP , van Helden HP , Tattersall JE
Ref : European Journal of Pharmacology , 471 :97 , 2003
Abstract : Organophosphate poisoning can result in seizures and subsequent neuropathology. One possible therapeutic approach would be to employ adenosine A(1) receptor agonists, which have already been shown to have protective effects against organophosphate poisoning. Using an in vitro model of organophosphate-induced seizures, we have investigated the ability of several adenosine A(1) receptor agonists to inhibit epileptiform activity induced by the organophosphate sarin, in the CA1 stratum pyramidale of the guinea pig hippocampal slice. Application of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) or the partial adenosine A(1) receptor agonists 2-deoxy-N(6)-cyclopentyladenosine (2-deoxy-CPA) and 8-butylamino-N(6)-cyclopentyladenosine (8-butylamino-CPA) abolished epileptiform activity in a concentration-related manner. The rank order of potency was CPA (IC(50) 4-5 nM) >2-deoxy-CPA (IC(50) 113-119 nM)=8-butylamino-CPA (IC(50) 90-115 nM). These data suggest that partial adenosine A(1) receptor agonists, which have fewer cardiovascular effects, should be further evaluated in vivo as potential treatments for organophosphate poisoning.
ESTHER : Harrison_2003_Eur.J.Pharmacol_471_97
PubMedSearch : Harrison_2003_Eur.J.Pharmacol_471_97
PubMedID: 12818696

Title : Therapeutic efficacy of the adenosine A(1) receptor agonist N(6)- cyclopentyladenosine (CPA) against organophosphate intoxication - Bueters_2002_Arch.Toxicol_76_650
Author(s) : Bueters TJ , Groen B , Danhof M , AP IJ , van Helden HP
Ref : Archives of Toxicology , 76 :650 , 2002
Abstract : The objective of the present study was to investigate whether reduction of central acetylcholine (ACh) accumulation by adenosine receptor agonists could serve as a generic treatment against organophosphate (OP) poisoning. The OPs studied were tabun ( O-ethyl- N-dimethylphosphoramidocyanidate), sarin (isopropylmethylphosphonofluoridate), VX ( O-ethyl- S-2-diisopropylaminoethylmethylphosphonothiolate) and parathion ( O, O-diethyl- O-(4-nitrophenyl)phosphorothioate). The efficacy of the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) against an OP intoxication was examined on the basis of the occurrence of clinical symptoms that are directly associated with such intoxication. CPA (1-2 mg/kg) effectively attenuated the cholinergic symptoms and prevented mortality in lethally tabun- or sarin-intoxicated rats. In contrast, CPA (2 mg/kg) proved to be ineffective against VX or parathion intoxication. Intracerebral microdialysis studies revealed that survival of sarin-poisoned and CPA-treated animals coincided with a minor elevation of extracellular ACh concentrations in the brain relative to the baseline value, whereas an 11-fold increase in transmitter levels was observed in animals not treated with CPA. In VX-intoxicated rats, however, the ACh amounts increased 18-fold, irrespective of treatment with CPA. The striatal acetylcholinesterase (AChE) activity following a lethal sarin intoxication was completely abolished in the vehicle-treated animals, whereas 10% and 60% AChE activity remained in animals treated with 2 mg/kg CPA 1 min after or 2 min prior to the poisoning, respectively. In VX-intoxicated animals the AChE activity in the brain was strongly reduced (striatum 10%, hippocampus 1%) regardless of the CPA treatment. These results demonstrate that CPA is highly effective against tabun or sarin poisoning, but fails to protect against VX or parathion. Survival and attenuation of clinical signs in tabun- or sarin-poisoned animals are associated with a reduction of ACh accumulation and with protection of AChE activity in the brain.
ESTHER : Bueters_2002_Arch.Toxicol_76_650
PubMedSearch : Bueters_2002_Arch.Toxicol_76_650
PubMedID: 12415428