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Antidotal effect of dihydroxyacetone against cyanide poisoning
Poster Session 1H. Risk Assessment products compared to control. Serum urea nitrogen and creatinine were significantly lower in dogs given either Parnidronate alone or in combination with calcitonin compared to control. Two control dogs were sacrificed on day 4 because of severe uremia In conclusion, Pamidronate can reverse D3-induced toxicosis and may be used to study the mechanisms of D3-induced toxicity in humans.
IOP1 G190 I SULFURDONORS AS CYANIDE ANTIDOTES S.l. Baskin *, D.W. Porter, G.A. Rockwood, J.A. Romano, R.C. Kaiser", C.M. CooJc2, A.L. Ternay 1r.2. } US Army Medical
ResearchInstituteof ChemicalDefense. Aberdeen ProvingGround, Maryland. Battelle Memorial Institute; 2Columbus. Ohio and UniversityofTexasat Arlington. Arlington. Texas. USA Antidotes for cyanide (CN) intoxication include the use of sulfane sulfur donors (SSD). To develop pretreatments that might be useful against CN, SSD with greater lipophilicity than thiosulfate were synthesized and assessed. This drug discovery program included an assessment of the SSD ability to protect mice against 2LD50'S of potassium cyanide (KCN) administered either 15 or 60 min following administration of SSD. Also, the ability of the compounds to improve recovery from CN intoxication was assessed by means of an inverted screen test 24 hrs post-CN. To study the mechanism of the SSD, the candidate compounds were examined in vitro for their effect on rhodanese and 3-mercaptopyruvate sulfurtransferase (MST) activity under increasing concentrations. Tests conducted on five candidate SSD (i.e., ICDI022, [3-hydroxy-2-pyridinyl 2-(3-N-methylamino) propylamino ethyldisulfide.3HCI]: ICDI584, [diethyltetrasulfide]; ICD1738, [N-(3-aminopropyl)-2-aminoethyl carbomethyloxy disulfide.2HCI]: ICD22 14, [2-aminoethyl-4-methoxyphenyl disulfide.HCI] and ICD2467, [bis(4-methoxyphenyl)disulfide]) demonstrated that altering the chemical substituent of the polysulfide modified the ability of the candidate SSD to protect against CN toxicity. At least two of the SSD provided 100% protection against 2LDso's of KCN. Three compounds were evaluated using locomotor activity as a measure of potential adverse behavioral effects. Several of the compounds appeared to inhibit rhodanese and MST. A previous cystathionase inhibition study performed in control and cyanide-treated rats does not appear to account for effects due to polysulfides observed in these mice cyanide protection studies. It is proposed that an alternative detoxification pathway, one not primarily involving the sulfurtransferases, may be important. Separate studies suggest that chemical reaction of CN and cystine to form the toxic metabolite, 2-iminothiazolidine-4-carboxylic acid. The SSD's tested may antagonize these metabolites. Although further studies that could elucidate the precise mechanisms need to be established, it is clear that these newly synthesized compounds provide a new class of rational anti-CN drugs.
IOP1G191 I ANTIDOTAL EFFECTOF DIHYDROXYACETONE AGAINSTCYANIDE POISONING
Hossein Niknahad *, Esmail Ghelichkhani. Faculty of Pharmacy,
Shira; University ofMedical Sciences, Shiraz, Fars, I.R., Iran
Potassium cyanide (eN) intoxication was found to be effectively antagonized by dihydroxyacetone (DHA), particularly if administered in combination with sodium thiosulfate, another CN antidote. Previously, we had shown that parental (i.p.) administration of DHA increased the LDso of subcutaneous CN injections (Niknahad H. & O'Brien P.I. 1996, Toxical. Appl. Pharmacal. 138,186-19/). In the present study, oral DHA (2&4 g/kg) given to mice 10 min before injection of CN (i.p.) increased the LD50 of CN (5.6 mglkg) by factors of 2.3 & 3.4, respectively. It was most effective if given 10 to 15 min before CN injection. Combination of pretreatment with oral DHA (4 glkg ) and post-treatment with sodium thiosulfate (I glkg)
85
increased the LDso of CN by a factor of 10.2. Furthermore, DHA given intravenously to rabbits 5 min after s.c. injection of CN increased the LD50of CN from 5.2 glkg to more than 15 mglkg, while thiosulfate (I glkg) given i.v. 5 min after CN injection increased the LD50 of CN only to 8.5 mglkg. DHA also prevented convulsions usually occur after CN intoxication. DHA is a physiological agent that is absorbed readily from GI tract and its reversible binding to CN in biological fluids and tissues is immediate. It can therefore prove a safe and effective antidote for cyanide.
IOP1 G1921
EFFECTOF PRALIDOXIME ON THE RESPIRATORY DISORDERS ASSOCIATED WITH ACUTEORGANOPHOSPHATE POISONING
P.N. Gueye *, O. Rivieros, F. Lofaso, F. Mellerio, A. Harf, E. Vicaut, F.J. Baud. Reanimation Toxicologique, Hop. F. Widal, Universite Paris Vll; ExplorationsFonctionnelles, Hop. H. Mondor, Universite
ParisXIl, Creteil, Paris, France Acute respiratory failure is an early complication of acute organophosphate poisoning (AOP). However, the efficacy of Pralidoxime in reversing these respiratory complications has never been clearly demonstrated. Methods: In 5 cases of organophosphate poisoning, we measured esophageal pressure (;1pes), gastric pressure (;1Pgas) and transdiaphragmatic pressure (;1Pdi) before Pralidoxime (TO) and after successively increasing doses (TI to T4). After an initial dose of 5 mglkg IV, Pralidoxime was administered at successively increasing doses over 40 min: Tl : 1.25 mg/kg, T2: 3.75 mglkg, T3 and T4: 7.5 mglkg. All patients were tracheally-intubated and spontaneously breathing. They all received atropine (3 ± mglh). Recordings of respiratory parameters were performed at TO, TI, T2, T3 and T4. Results: All patients were comatose (GCS: 5 ± 3), and were tracheally intubated for acute respiratory failure. The plasma cholinesterase level was 1 ± 1 U/mL. Breathing was characterized by an increased respiratory rate (f: 29 ± 41min), a decrease in VT (300 ± 167 mL) as well as VE (6 ± 4 Umin), a decrease in inspiratory effort (;1Pes 9 ± 6 cm H20, ;1Pgas: I ± I cm H20) and a decrease in diaphragmatic muscle foree (;1Pdi: II ± 5 ern H20). There was no significant change in any ventilatory parameters after successive and increasing doses of Pralidoxine. No patient was extubated after Pralidoxime. The duration of mechanical ventilation was 7 ± 8 days. No patients died. Conclusion: I) Diaphragmatic muscle weakness seems to be an important cause of respiratory failure during AOP, 2) In this small group of patients, Pralidoxime at high doses did not improve the organophosphate-induced respiratory disorders 3) The respiratory efficacy of this antidote remains to be demonstrated .
PIll. Risk Assessment
IPi H1931
STRATEGY FOR ASSESSMENT OF CUTANEOUS AND OCULARIRRITATION OF INTERMEDIATE PRODUCTS OF SYNTHESIS
C. Robles *, 1. Unkovic, F.Lacheretz. Departmentof Toxicology and
General Pharmacology, SANOFl Recherche. 34184 Montpellier, France For many years, the chemicals, and among them, the intermediate products of synthesis of the drugs under development, have been forming the subject matter of studies on animals, intended for documenting the safety data sheets used by all people who have to handle these chemicals. Our concern has been to design a study protocol providing maximum safety to man, while maintaining the ethical use in the
IOP1 G190 I SULFURDONORS AS CYANIDE ANTIDOTES S.l. Baskin *, D.W. Porter, G.A. Rockwood, J.A. Romano, R.C. Kaiser", C.M. CooJc2, A.L. Ternay 1r.2. } US Army Medical
ResearchInstituteof ChemicalDefense. Aberdeen ProvingGround, Maryland. Battelle Memorial Institute; 2Columbus. Ohio and UniversityofTexasat Arlington. Arlington. Texas. USA Antidotes for cyanide (CN) intoxication include the use of sulfane sulfur donors (SSD). To develop pretreatments that might be useful against CN, SSD with greater lipophilicity than thiosulfate were synthesized and assessed. This drug discovery program included an assessment of the SSD ability to protect mice against 2LD50'S of potassium cyanide (KCN) administered either 15 or 60 min following administration of SSD. Also, the ability of the compounds to improve recovery from CN intoxication was assessed by means of an inverted screen test 24 hrs post-CN. To study the mechanism of the SSD, the candidate compounds were examined in vitro for their effect on rhodanese and 3-mercaptopyruvate sulfurtransferase (MST) activity under increasing concentrations. Tests conducted on five candidate SSD (i.e., ICDI022, [3-hydroxy-2-pyridinyl 2-(3-N-methylamino) propylamino ethyldisulfide.3HCI]: ICDI584, [diethyltetrasulfide]; ICD1738, [N-(3-aminopropyl)-2-aminoethyl carbomethyloxy disulfide.2HCI]: ICD22 14, [2-aminoethyl-4-methoxyphenyl disulfide.HCI] and ICD2467, [bis(4-methoxyphenyl)disulfide]) demonstrated that altering the chemical substituent of the polysulfide modified the ability of the candidate SSD to protect against CN toxicity. At least two of the SSD provided 100% protection against 2LDso's of KCN. Three compounds were evaluated using locomotor activity as a measure of potential adverse behavioral effects. Several of the compounds appeared to inhibit rhodanese and MST. A previous cystathionase inhibition study performed in control and cyanide-treated rats does not appear to account for effects due to polysulfides observed in these mice cyanide protection studies. It is proposed that an alternative detoxification pathway, one not primarily involving the sulfurtransferases, may be important. Separate studies suggest that chemical reaction of CN and cystine to form the toxic metabolite, 2-iminothiazolidine-4-carboxylic acid. The SSD's tested may antagonize these metabolites. Although further studies that could elucidate the precise mechanisms need to be established, it is clear that these newly synthesized compounds provide a new class of rational anti-CN drugs.
IOP1G191 I ANTIDOTAL EFFECTOF DIHYDROXYACETONE AGAINSTCYANIDE POISONING
Hossein Niknahad *, Esmail Ghelichkhani. Faculty of Pharmacy,
Shira; University ofMedical Sciences, Shiraz, Fars, I.R., Iran
Potassium cyanide (eN) intoxication was found to be effectively antagonized by dihydroxyacetone (DHA), particularly if administered in combination with sodium thiosulfate, another CN antidote. Previously, we had shown that parental (i.p.) administration of DHA increased the LDso of subcutaneous CN injections (Niknahad H. & O'Brien P.I. 1996, Toxical. Appl. Pharmacal. 138,186-19/). In the present study, oral DHA (2&4 g/kg) given to mice 10 min before injection of CN (i.p.) increased the LD50 of CN (5.6 mglkg) by factors of 2.3 & 3.4, respectively. It was most effective if given 10 to 15 min before CN injection. Combination of pretreatment with oral DHA (4 glkg ) and post-treatment with sodium thiosulfate (I glkg)
85
increased the LDso of CN by a factor of 10.2. Furthermore, DHA given intravenously to rabbits 5 min after s.c. injection of CN increased the LD50of CN from 5.2 glkg to more than 15 mglkg, while thiosulfate (I glkg) given i.v. 5 min after CN injection increased the LD50 of CN only to 8.5 mglkg. DHA also prevented convulsions usually occur after CN intoxication. DHA is a physiological agent that is absorbed readily from GI tract and its reversible binding to CN in biological fluids and tissues is immediate. It can therefore prove a safe and effective antidote for cyanide.
IOP1 G1921
EFFECTOF PRALIDOXIME ON THE RESPIRATORY DISORDERS ASSOCIATED WITH ACUTEORGANOPHOSPHATE POISONING
P.N. Gueye *, O. Rivieros, F. Lofaso, F. Mellerio, A. Harf, E. Vicaut, F.J. Baud. Reanimation Toxicologique, Hop. F. Widal, Universite Paris Vll; ExplorationsFonctionnelles, Hop. H. Mondor, Universite
ParisXIl, Creteil, Paris, France Acute respiratory failure is an early complication of acute organophosphate poisoning (AOP). However, the efficacy of Pralidoxime in reversing these respiratory complications has never been clearly demonstrated. Methods: In 5 cases of organophosphate poisoning, we measured esophageal pressure (;1pes), gastric pressure (;1Pgas) and transdiaphragmatic pressure (;1Pdi) before Pralidoxime (TO) and after successively increasing doses (TI to T4). After an initial dose of 5 mglkg IV, Pralidoxime was administered at successively increasing doses over 40 min: Tl : 1.25 mg/kg, T2: 3.75 mglkg, T3 and T4: 7.5 mglkg. All patients were tracheally-intubated and spontaneously breathing. They all received atropine (3 ± mglh). Recordings of respiratory parameters were performed at TO, TI, T2, T3 and T4. Results: All patients were comatose (GCS: 5 ± 3), and were tracheally intubated for acute respiratory failure. The plasma cholinesterase level was 1 ± 1 U/mL. Breathing was characterized by an increased respiratory rate (f: 29 ± 41min), a decrease in VT (300 ± 167 mL) as well as VE (6 ± 4 Umin), a decrease in inspiratory effort (;1Pes 9 ± 6 cm H20, ;1Pgas: I ± I cm H20) and a decrease in diaphragmatic muscle foree (;1Pdi: II ± 5 ern H20). There was no significant change in any ventilatory parameters after successive and increasing doses of Pralidoxine. No patient was extubated after Pralidoxime. The duration of mechanical ventilation was 7 ± 8 days. No patients died. Conclusion: I) Diaphragmatic muscle weakness seems to be an important cause of respiratory failure during AOP, 2) In this small group of patients, Pralidoxime at high doses did not improve the organophosphate-induced respiratory disorders 3) The respiratory efficacy of this antidote remains to be demonstrated .
PIll. Risk Assessment
IPi H1931
STRATEGY FOR ASSESSMENT OF CUTANEOUS AND OCULARIRRITATION OF INTERMEDIATE PRODUCTS OF SYNTHESIS
C. Robles *, 1. Unkovic, F.Lacheretz. Departmentof Toxicology and
General Pharmacology, SANOFl Recherche. 34184 Montpellier, France For many years, the chemicals, and among them, the intermediate products of synthesis of the drugs under development, have been forming the subject matter of studies on animals, intended for documenting the safety data sheets used by all people who have to handle these chemicals. Our concern has been to design a study protocol providing maximum safety to man, while maintaining the ethical use in the