Adamantyl tenocyclidines--adjuvant therapy in poisoning with organophosphorus compounds and carbamates.
The objective of this study was to evaluate the efficacy of thienyl phencyclidine (tenocyclidine, TCP) and its newly synthesized adamantyl derivatives containing piperidine (TAPIP), pyrolidine (TAPIR) and morpholine (TAMORF) groups, which were tested with or without standard therapy in mice poisoned with organophosphates (OPs) and carbamates. These compounds with potential activity at the N-methyl- D-aspartate and muscarinic receptors showed low acute toxicity, having LD50 values varying from 106.00 mg/kg (TCP) to >504.00 mg/kg body weight (TAMORF). TCP and its adamantyl derivatives were administered intraperitoneally (2.5 mg/kg body weight) together with atropine (10.0 mg/kg body weight) and with or without 1/4 LD50 of the oxime HI-6. Each compound administered with atropine had a therapeutic effect against poisoning with carbamates propoxur, aldicarb and Ro 02-0683 (protective ratio of tenocyclidines was from 3.99 LD50 of aldicarb to >16.00 LD50 for propoxur). However, the efficacy of those compounds in combination with atropine was lower against poisoning with the OP insecticide dichlorvos (DDVP) and chemical warfare agents soman and tabun. In soman-poisoned mice, the best therapeutic effects were obtained with the combination of HI-6 plus atropine and test compounds, with protective ratios being from 5.40 to 7.12 LD50 of soman. The results suggest that TCP and adamantyl tenocyclidines could be used in combination with atropine as antidotes in carbamate poisoning and as adjuvant therapy to HI-6 and atropine in soman poisoning.
Skare
Danko
D
Institute Ruder Bosković, Bijenicka c. 54, 10000 Zagreb, Croatia. skare@rudjer.irb.hr
Radić
Bozica
B
Lucić
Ana
A
Peraica
Maja
M
Domijan
Ana-Marija
AM
Milković-Kraus
Sanja
S
Bradamante
Vlasta
V
Jukić
Ivan
I
D000218:Adamantane / Q000031:analogs & derivatives*; D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D001285:Atropine / Q000627:therapeutic use; D002219:Carbamates / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008808:Mice, Inbred CBA; D062025:Organophosphate Poisoning; D010091:Oximes; D011041:Poisoning / Q000517:prevention & control*; D011726:Pyridinium Compounds / Q000737:chemistry / Q000627:therapeutic use*
D000931:Antidotes; D002219:Carbamates; D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; D001285:Atropine; C022870:asoxime chloride; D000218:Adamantane