Despite improvements to intensive care management and specific pharmacological treatments (atropine, oxime, diazepam), the mortality associated with organophosphate (OP) poisoning has not substantially decreased. The objective of this examination was to describe the role of fresh frozen plasma (FFP) in acute OP poisoning. After a deliberate ingestion of malathion, a 55-year-old male suffering from miosis, somnolence, bradycardia, muscular fasciculations, rales on auscultation, respiratory insufficiency, as well as from an inhibition of red blood cell acetylcholinesterase (AChE) and plasma butyrylcholinesterase (BCHE), was admitted to hospital. Malathion was confirmed in a concentration of 18.01 mg L-1. Apart from supportive measures (including mechanical ventilation for four days), antidotal treatment with atropine, oxime - pralidoxime methylsulphate (ContrathionR), and diazepam was administered, along with FFP. The potentially beneficial effects of FFP therapy included a prompt increase of BCHE activity (from 926 IU L-1 to 3277 IU L-1; reference range from 7000 IU L-1 to 19000 IU L-1) and a reduction in the malathion concentration, followed by clinical recovery. Due to BCHE replacement, albumin content, and volume restitution, FFP treatment may be used as an alternative approach in patients with acute OP poisoning, especially when oximes are not available.
This study was undertaken to examine the influence of atropine, oximes and benzodiazepine on organophosphate-induced delayed polyneuropathy (OPIDP) in hens, which were poisoned with diisopropylfluorophosphate (DFP). The birds were treated with a standard neuropathic dose of DFP (1.1 mg/kg, s.c.), which produced typical signs of OPIDP. The development of OPIDP was observed within the followings 22 days. All drugs were given subcutaneously (s.c.), intramuscularly (i.m.) or intraperitoneally (i.p.), 20 min before the poison. The results obtained have shown that atropine (20 mg/kg, i.p.) only in combination with oxime TMB-4 (15 mg/kg, i.m.) produced significant improvement of OPIDP symptoms in comparison with positive control. Clinical signs and symptoms of OPIDP in the group which was treated with atropine (20 mg/kg, i.p.), TMB-4 (15 mg/kg, i.m.) and midazolam (2.5 mg/kg, i.m.) were more improved than that in the presence of a combination of atropine and TMB-4. The results of these experiments have shown that it is possible to prevent the development of DFP-induced OPIDP in hens by treatment with atropine and TMB-4 or atropine, TMB-4 and midazolam when given before DFP.
The efficacy of the oxime HI-6 was studied as a treatment for organophosphorus poisoning. HI-6 was given four times daily as a single intramuscular injection of 500 mg accompanied by atropine and diazepam therapy. Oxime treatment was started on admission and continued for a minimum of 48 h and a maximum of 7 d. HI-6 rapidly reactivated human blood acetylcholinesterase inhibited by dimethoxy organophosphorus compounds, while the dimethoxy-inhibited enzyme was mainly resistant to the treatment by HI-6. Although both HI-6 and pralidoxime chloride reactivated the red blood cell cholinesterase in quinalphos-poisoned subjects, the return of enzyme activities was more rapid following the use of HI-6. The general improvement of poisoned patients, which was sometimes more rapid than the rise of acetylcholinesterase activity, pointed to direct pharmacological effects of HI-6. No undesirable side-effects were noted in patients when HI-6 plasma concentrations were maintained at levels far above the 'therapeutic' concentration for up to 7 d.
Title: Soman intoxication-induced changes in serum acute phase protein levels, corticosterone concentration and immunosuppressive potency of the serum Sevaljevic L, Marinkovic S, Bogojevic D, Matic S, Boskovic B Ref: Archives of Toxicology, 63:406, 1989 : PubMed
We have studied the effect of soman intoxication on serum acute phase reactants (APR) levels, and the relationship of the APR and corticosterone concentrations and the immunosuppressive activity of the serum. One day after the injection of 1.8 LD50 soman the concentrations of alpha 2-macroglobulin (alpha 2-MG) and alpha 1-acid glycoprotein (AGP) in the serum of antidote protected rats increased 4- and 7-fold, respectively, whereas those of hemopexin (Hx), haptoglobin (Hp) and cysteine protease inhibitor (CPI) were two to three times higher than in the controls. A similar magnitude of increase of serum acute phase reactants levels was observed when 0.3 LD50 soman was administered at 24-h intervals over the 5-day period. The relationship of changes in the APR concentration, corticosterone level and immunosuppressive activity of the serum was also comparable to that observed in the acute phase response to tissue injury.
Title: HI-6 in man: blood levels, urinary excretion, and tolerance after intramuscular administration of the oxime to healthy volunteers Kusic R, Boskovic B, Vojvodic V, Jovanovic D Ref: Fundamental & Applied Toxicology, 5:S89, 1985 : PubMed
After intramuscular administration of graded doses of HI-6 (62.5, 125, 250, and 500 mg) to 22 healthy men, it has been established that therapeutic concentrations of the oxime in plasma, arbitrarily taken as 4 micrograms/ml, were achieved by doses of 250 and 500 mg in about 5 min, and maintained from 2 to 3 hr. The two lowest doses have not been satisfactory in this respect. Of the total doses injected, from 56.3 to 62% of HI-6 was excreted into urine unchanged during the first 6 hr. No side-effects were reported by the subjects, nor revealed by clinical or laboratory tests during the study. Exceptional tolerance of HI-6 in man found in this study, along with its high efficiency proven in experimental poisoning by sarin, VX, and soman, make it the most promising oxime aimed at the treatment of human poisoning by known chemical warfare nerve agents.
Title: Effects of Sarin, Soman and Tabun on plasma and brain aliesterase activity in the Rat Boskovic B, Jokanovic M, Maksimovic M Ref: In: Cholinesterases, fundamental and applied aspects : proceedings of the Second International Meeting on Cholinesterases, (Brzin M, Barnard EA, Sket D, Eds) De Gruyter:365, 1984 : PubMed
Acute sc toxicity of soman increased in the order, mice----rats----guinea pigs----dogs, being 12.6 times more toxic to dogs (LD50 = 0.05 mumol/kg) than to mice. It was 2.8 times more toxic than tabun to mice and 35 times more toxic to dogs. HI-6 was the least toxic and had similar toxicity values to the four animal species studied and HGG-12 the most toxic of the three oximes used. HGG-12 has shown the greatest interspecies variation (rats:dogs = 1:19.5). HI-6, HGG-12, and PAM-2 Cl (in conjunction with atropine and diazepam) revealed the best protective effect in soman-poisoned dogs, with the respective protective indices of 9, 6.3, and 3.5, followed by guinea pigs. In tabun poisoning the best, but relatively low, protective effect was found only in guinea pigs. The introduction of diazepam increased the protective effects of atropine-oxime combination in soman and tabun poisoning by 10 to 80%. We suggest that the high toxicity of soman and low toxicity of HI-6 may be anticipated in man. The inefficiency of HI-6, HGG-12, and PAM-2 Cl in tabun poisoning points either to the search of new compounds or to the use of the mixture of the oximes found to be effective against the known chemical warfare nerve agents.
Title: [Present trends in the therapy of poisoning by nerve poisons for warfare] Kusic R, Boskovic B Ref: Vojnosanit Pregl, 41:364, 1984 : PubMed
Title: Poster 77. On the in vitro interaction of sarin and soman with PAM-2, HI-6 and HGG-12 Rakin D, Tokovic B, Boskovic B Ref: In: Cholinesterases, fundamental and applied aspects : proceedings of the Second International Meeting on Cholinesterases, (Brzin M, Barnard EA, Sket D, Eds) De Gruyter:, 1984 : PubMed
Title: The influence of 2-/o-cresyl/-4 H-1 : 3 : 2-benzodioxa-phosphorin-2-oxide (CBDP) on organophosphate poisoning and its therapy Boskovic B Ref: Archives of Toxicology, 42:207, 1979 : PubMed
The aim of the experiments was to obtain more information on the toxicity of organophosphates and protection against them. Pretreatment of mice with CBDP increased the s.c. toxicity of soman 19.1-fold, and its i.p. toxicity 17.8-fold. The protective effect of atropine and the oximes HS-3, HS-6 and HI-6 in soman poisoning was much greater in CBDP pretreated than in control animals. Atropine + HI-6 raised the s.c. LD50 of soman in the CBDP pretreated animals from 6.8 micrograms/kg to 166 micrograms/kg (PI = 24.3), but in control animals the i.p. LD50 was only raised from 370 micrograms/kg to 608 micrograms/kg (PI = 0.6). CBDP inhibited blood and brain AChE activity, but had no effect on aliesterase (AE) activity in plasma, liver and brain of mice in vivo. CBDP increased s.d. toxicities of sarin 11-fold, of tabun 5-fold and of VX 0.24-fold. The protective index of atropine + HS-3 in sarin poisoning, as in the case of soman poisoning, was much higher in CBDP pretreated than in control animals (20.1 : 13.6), only slightly higher in tabun poisoning (4.3 : 3.4) and in the case of VX poisoning lower in CBDP pretreated than in control animals (32 : 47). The results indicate that CBDP potentiates soman, sarin and tabun toxicities mainly by blocking their binding to non-specific sites in the body.
Title: [Drugs and methods of first aid, resuscitation and treatment of acute poisoning] Kusic R, Boskovic B, Rosic N Ref: Arh Hig Rada Toksikol, 30:167, 1979 : PubMed
Title: [Treatment of acute poisoning -- methods and steps in hospital admission] Kusic R, Raicevic B, Rosic N, Boskovic B Ref: Arh Hig Rada Toksikol, 30:173, 1979 : PubMed
Title: [Pharmacological and toxicological properties of modern chemical warfare poisons causing irritation (type CS, CR)] Rosic N, Kusic R, Boskovic B, Vojvodic V Ref: Vojnosanit Pregl, 31:345, 1974 : PubMed
Title: [The resorption rate of TMB-4(Trimedoxime) Cl2 antidote after intramuscular administration by injection, syringe and autoinjector in control and poisoned animals] Vojvodic V, Boskovic B, Vojvodic M Ref: Vojnosanit Pregl, 30:239, 1973 : PubMed
Title: Ageing and reactivation of acetylcholinesterase inhibited with soman and its thiocholine-like analog Boskovic B, Maksimovic M, Minic D Ref: Biochemical Pharmacology, 17:1738, 1968 : PubMed
