II. INTERNATIONAL SYMPOSIUM 1 INIS-mf--11233 %. -'-;; -r^ >* CHEIATING AGENTS IN^PHARMACOLOGY, TOXICOLOGY AND THERAPEUTICS PILSEN. 12 14 8 1987 2nd International Syaposiua CHELATING AGENTS IN PHARMACOLOGY, TOXICOLOGY AND THERAPEUTICS Pilsen, 12.-14. 8. 1987 organized by THE CZECHOSLOVAK NEOICAL SOCIETY J.E.PURKYNt The Czechoslovak Pharmacological Society in cooperation with THE DEPARTMENT OF PHARMACOLOGY Faculty of Medicine, Charles University Pilsen THE INSTITUTE OF HY6IENE AND EPIDEMIOLOGY Prague Organizing Coeaittee V. Eybl President 0. Maitzovi Secretary D. Caisovi Meabera M. Cikrt M. Koutenski J. Koutensk? J. Sykora A. Zechaeister B This volume contains all abstracts of papers accepted till 15th April 1987 by the Organizing Committee. These abstracts are photographically repro- duced from the original forms submitted by the authors. The authors are responsible for the content and the grammatical style of their abstracts. The papers are arranged in alphabetical order of the authors names. \ ORAL COMMUNI CATIONS EFFECTS OF COMPLEXING THIOLS ON BILIARY EXCRE- TION OF LEAD IN THE RAT J.ALEXANDER, J.AASETH Department of Toxicology, National Institute of Public Health, Geitmyrsvn. 75, 0462 Oslo 4, Norway," Hedemark Central Hospital, Elverum, Norway The fecal route is an important excretory path- way for lead in humans, and may as in the rat be derived from biliary excreted lead. Previous studies indicate that lead is excreted into bi- le by a glutathione dependent mechanism (Ale- xander et al.). The efficiency of therapeutic chelating agents may in addition to enhanced urinary metal excretion also work via an en- creased biliary excretion. Several chelating agents were therefore examined: diethyldithio- carbamate (DDC) BAL, DMSA, N-acetylpenicillami- ne and penicillamine. DDC initially inhibited biliary lead excretion while all of the other J compounds caused an increased biliary lead ex- j cretion in lead exposed rats. Penicillamine 1 was the most efficient compound. Their media- ; nism of action is not clear as their effects .< may either be a result of lead-complexation h within the cell followed by excretion of the complex or indirectly by influencing glutathio- ne metabolism. Increased levels of glutathione in the liver may cause an enhanced lead excre- tion into bile. To prevent reabsorption of bi- liary excreted lead in the gut it is suggested to combine treatment with penicillamine with a nonabsorbable lead chelating agent. Alexander,J., Aaseth, J. and Mikalsen, A. Acta Pharmacol. Toxicol. Suppl. 59, 486-489, 1986. CHELAT1ON OF CADMIUM IN VIVO. Oie Andersen Department of Environmental Medicine, Odense University, 3.B. Winsl#ws Vej 19, DK-5000 Odense C, Denmark. Acute human Cd intoxication is always due to oral or pulmonary exposure, and immediate mortality is caused by gastrointestinal (g.i.) or pulmonary epithelial damage. However, secondary hepatic and renal damage may develop. The acute toxicity of Cd and effects of chelators thereon has mainly been studied experimentally after parenteral exposures, where acute mortality is due to hepatic necrosis. The present work demonstrated that chelating agents could affect the acute toxicity of cadmium quite differently depending on the administration route of both cadmium and chelator. The best example is DDC, which after parenteral administration of both DDC and cadmium is an efficient antidote, but which after oral admini- stration of cadmium increased the acute toxicity of cadmium quite dramatically. Effects of chelators on acute cadmium toxicity was investigated after either oral or intraperitoneal (ip) exposure to both chelator and cadmium. After comparing effects of about 20 chelators, including a number of polyaminopolycarboxylic acids and various derivatives of BAL, DDC and penicillamin, DMSA was found to be superior after oral exposure, while TTHA was superior after ip exposure. Both reduced the retention of cadmium efficiently, and they acted synergistically when administered together (DMSA orally and TTHA ip) 15 min after a highly toxic oral dose of cadmium. Our results corroborate and extend those of Mark Jones and define a very effective chelation antidote treatment of oral cadmium intoxication, which also minimize cadmium retention and thus the risk of secondary systemic toxicity. METABOLIC STUDIES OF MESO-DMSA IN HUMANS Ik VASKEN APOSHIAN, RICHARD M. MAIORINO AND DANA F. PERRY University of Arizona, Tucson, Arizona, USA The presence of oxidized species of meso-2,3,-dimercap- tosuccinic acid in human urines has been determined and quantified. Unaltered DMSA was determined by derivatization of the thiol groups with monobromobirnane (BB). Total DMSA (unaltered and altered) was determined by electrolytic reduction followed by BB derivatization. The bimane deriva- tives were identified and quantified by HPLC and fluorescence. Six male human volunteers were given lOmg DMSAAg po after which their urines were collected during a 14hr period. At the time of writing of this abstract, studies of the urine of three volunteers have been completed. The unaltered DMSA excreted in the urine 14 hrs after DMSA administraton averaged 2.62% of the given dose; the altered DMSA was 20.98%. The peak of excretion of unaltered DMSA and altered DMSA occurred at 2 hrs and 4 hrs, respectively. Based on human and rabbit studies, the * altered DMSA consists of disulfide and tetrasulfide forms of 5 DMSA. The urines are also being analyzed for Cu, Zn and Pb { content. These new methods for the determination of the c dithiols and their oxidized forms should lead to a better i understanding of the metabolic properties of these \ increasingly important, orally effective metal mobilizing agents. EFFECT OF DMPS AND D-PENICILLANINE ON THE LEVEL OF LIPID PEROXIDATION PRODUCTS IN FiETAL-POI SONED RATS L.BENOV, O.PIONOUICH, I.BENCHEV Department of Biophysics, University School of Medicine, 5800 Pleven, Bulgaria The level of lipid peroxidation prooucts (con- jugated diens, lipid hydroperoxides, fluorescence products and malondialdehyde) and the activities of some enzymes protecting the cell against activa- ted oxygen have been studied in copper and mercury poisoned rats, treated with 2,3-dimercapto-1-pro- pane sulfonic acid (DFIPS) or D-penicillamine (DP). It has been found that both thiols significantly inactivated superoxide dismutase in blood, liver ) and kidney in healthy as uell as in metal-poisoned ] rats. The treatment of copoer-poisoned rats with : DMPS or DP caused increase of ("IDA and fluorescence 5, products in the blood. In the liver, houever, DP afforded protection against lipid peroxidation but DHPS did not. Decrease of the level of the lipid peroxidation products has been observed also in the liver of mercury-poisoned rats treated with DPIPS or DP. Neither of the antidotes exerts effect on the level of the lipid peroxidation products in the kidney. 10 CANCER PREVENTION BY CHELATION THERAPY W.BLUMER General Practice, Netstal, Switzerland. The cancer mortality among 331 adult persons living adjacent to an automobile road was found to be 9 times higher than in a traffic-free section of the same town. The inhabitants residing near the road had suffered also very often from haedaches, fatigue, stomach ailments, depressive conditions, nervous trou- bles and tablets-misuse. The existence of small lead deposits as well as the healthimpairing effect of lead were demonstrated by measurements of lead and delta- aninolaevulinic acid in urine. After treatment with Calcium-Dinatrium-EDTA in order to eliminate lead the patients were cured and the lead content as well as the amount of deltaaminolaevulinic acid became normal. 59 of the residents nead the road had been treated in this way. Only one of these later died of cancer. Of 172 persons, who were not treated, 30 died of cancer, or ten times more percentage-wise. The concentrations of airborne lead and carcinogenic hydrocarbons in sedimented dust and in suspended dust were much grea- ter along the automobile road than in the traffic- free section. These findings together with many other reports in the medical literature lead to the suspi- cion that lead in gasoline, combined with other carcinogenic substances in automotive exhaust gases, increases the incidence of cancer. 11 CHELATION THERAPY IN OCCLUSIVE ARTERIOSCLEROSIS 0. BRflCKNEROVA 3 Internal Clinic, Purkyni University, Brno, CSSR In the course of the last 20 years fleJSDTA was applied in i.v. drop Infusions to a group of 65 patients( 51 men + 14 women) suffering from ocelusive arterial disease of the lower extremities. Each infusion contained 3 gme of Ka9EDTA (CHELATON III) dissolved in 500 ml of 5% fructose and lasted about 4 hours. Each cure consisted of 30 Infusions, one dai- ly, for 5 day8''each week. The whole cure lasted 6 weeks. In some patients the therapy waa repe- ated after a pause of 6 months. At the beginning of treatment the average age was 54 in men and 63 in women. In most of the patients multiple atherosclerotic lesions were present not only in the arteries of the limbs but also in the coronary and/or cerebral arte- ries* This limited the chance of surgical recon- struction* The therapy was well tolerated and an amelio- ration waa achieved namely in prolongation of the walking distance in stage II ( Fontaine)and the disappearance of rest-pain in stage III* In stage IV the results were less favourable. After long-term observation 34% of the group are ali- ve, 51% died and 15% are loat of evidence. The mechanisme of action is explained by some authors by disintegration of atherosclerotic pla- oues and elimination of metastati.s caloiua fram deposits which in not accompained by ceteoporo**. sis. 12 OBJECTIVE EVIDENCE OF THE EFFICACY OF CHELATION THERAPY BY RAOIONUCLIOE STUDIES IN PATIENTS WITH HEART AND BRAIN DISORDERS. H.R. Casdorph, M.D.,Ph.D., Casdorph Cinic, Long Beach, CA USA Eighteen patients with documented Atherosclerotic Heart Disease were studied using .Technetlun 99a to measure lefc ventricular ejection fraction at rest before and after the administration of 20 treatments of EDTA Chelation Therapy. A statistically significant improvement in the left ventricular ejection fraction Qccured in the treated group of patients.