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Biomedical subjects

J G Clement

Publications and source records attributed to J G Clement.

At least 73 records · Page 4Linked to original sources
PubMed1988

The acetylcholinesterase reactivator HI-6 (1-[[[4-(aminocarbonyl)pyridinio]methoxyl]methyl]- 2-[(hydroxyimino)methyl]-pyridinium dichloride): a comparative study of HI-6 samples from various sources.

A comparison of the chemical purity, toxicology and potency of HI-6 (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2- [(hydroxyimino)methyl]-pyridinium dichloride) obtained from various sources (Canada, Israel, Yugoslavia, The Netherlands, United Kingdom) was performed. There were no significant differences between HI-6 obtained from Israel, Yugoslavia, The Netherlands and Canada regarding their potency, when combined with atropine, as an antidote of organophosphate poisoning. HI-6 obtained from the United Kingdom was significantly more toxic and less potent than any of the other HI-6 samples. In addition, the results of this study showed that there was no significant difference between HI-6 prepared as a laboratory batch and HI-6 prepared commercially with regards to chemical purity, toxicology or potency.

Animals↗
PubMed1987

Role of endogenous opioids in soman (pinacolyl methylphosphonofluoridate)-induced antinociception.

The effect of soman poisoning on the levels of methionine enkephalin and beta-endorphin in mice and rats were determined. Soman poisoning produced no significant effect on methionine enkephalin levels in the striatum of rats or mice or beta-endorphin levels in the pituitary gland of mice. In rats beta-endorphin levels were significantly reduced 24 hr post soman poisoning, but returned to control levels by 48 hr. In vitro, the hydrolysis of leucine enkephalin by aminopeptidase was virtually complete by 30 min and found to be the major route of degradation. The release of TYR-GLY-GLY in the presence or absence of puromycin (10 microM) was found to be low (less than or equal to 2.0%). A minor effect on TYR release in the presence of GLY-GLY-PHE-MET (50 microM) was insignificant. Preincubation of mouse striatum homogenates with soman (1 or 10 microM) did not inhibit the hydrolysis of leucine enkephalin. These results suggest that the long term antinociception following soman exposure is not due to either altered concentration of endogenous opioid-like substances or inhibition of the enzymes responsible for their degradation.

Animals↗
PubMed1987

Comparison of serum concentrations of the acetylcholinesterase oxime reactivators HI-6, obidoxime, and PAM to efficacy against sarin (isopropyl methylphosphonofluoridate) poisoning in rats.

A comparison of serum concentrations of the oximes HI-6 [1-(((4-aminocarbonyl)-pyridino)methoxy)methyl)-2(hydroxy imino)methyl- pyridinium dichloride], PAM [2-[hydroxyimino)methyl-1-methylpyridinium chloride], and obidoxime [1,1'-(oxybis(methylene]bis(4-((hydroxyimino) methyl)-pyridinium dichloride] to the efficacy against sarin (350 micrograms/kg; sc) lethality was evaluated in rats. The oximes were administered prophylactically by means of Alzet osmotic minipumps. Atropine (17.4 mg/kg; im) was administered immediately following sarin (350 micrograms/kg; sc) administration. At serum concentrations of 3.6, 3.6, and 3.3 micrograms/ml for HI-6, obidoxime, and PAM, respectively, the 24-hr mortality following sarin poisoning was 0, 90, and 20%. The serum oxime concentrations (ED50 values) for HI-6, obidoxime, and PAM against a 3 LD50 dose of sarin were 0.72, 9.05, and 2.56 micrograms/ml, respectively. HI-6 was determined to be the most efficacious oxime when combined with atropine against sarin poisoning followed in order by PAM and obidoxime.

Acetylcholinesterase↗
PubMed1987

Stereoisomers of soman (pinacolyl methylphosphonofluoridate): inhibition of serum carboxylic ester hydrolase and potentiation of their toxicity by CBDP (2-(2-methylphenoxy)-4H-1,3,2-benzodioxaphosphorin-2-oxide) in mice.

The interaction of C(+/-)P(+/-)-soman (pinacolyl methylphosphonofluoridate) and its individual stereoisomers with serum carboxylic-ester hydrolase and potentiation of their toxicity by a carboxylic-ester hydrolase inhibitor CBDP (2-(2-methylphenoxy)-4H-1,3,2-benzodioxaphosphorin-2-oxide) was investigated. C(+/-)P(+/-)-Soman and the individual stereoisomers all inhibited purified mouse serum carboxylic-ester hydrolase to different degrees. C(+/-)P(+/-)-Soman and the C(-)P(-)- and C(+)P(-)-isomers had Ki values of 30.6, 18.7, and 35.7 nM, respectively, and C(-)P(+)- and C(+)P(+)-isomers had Ki values of 1412 and 2523 nM, respectively. In toxicity experiments CBDP (0.5 mg/kg; iv 1 hr prior to soman) pretreatment potentiated the toxicity of C(+/-)P(+/-)-, C(+)P(-)-, and C(-)P(-)-soman to a similar degree. Thus, it appears that the toxic stereoisomers of soman have a similar affinity for mouse serum carboxylic-ester hydrolase, and CBDP pretreatment does not enhance selectively the toxicity of one stereoisomer over the other.

Animals↗
PubMed1987

Efficacy of a combination of acetylcholinesterase reactivators, HI-6 and obidoxime, against tabun and soman poisoning of mice.

The bispyridinium oxime HI-6, 1-((((4-amino-carbonyl)pyridinio)methoxy) methyl)-2-(hydroxyimino)methyl)pyridinium dichloride monohydrate, combined with atropine is an effective treatment for soman (pinacolyl methylphosphonofluoridate) poisoning but is relatively ineffective against tabun (ethyl N-dimethyl phosphoroamidocyanidate) poisoning in mice. This contrasts with those results obtained using the bispyridinium oxime obidoxime[1,1'-(oxy bis(methylene)) bis(4-(hydroxyimino)methyl) pyridinium dibromide]. The purpose of this study was to investigate the efficacy of the combination of HI-6 and obidoxime plus atropine against poisoning by tabun and soman in mice. The combination of ineffective single doses of obidoxime (5 or 10 mg/kg) and HI-6 (25 or 50 mg/kg) improved the treatment of tabun poisoning over either oxime alone. Combinations employing higher concentrations of obidoxime (25 or 50 mg/kg) and HI-6 (100 or 200 mg/kg) resulted in significant toxicity in the absence of organophosphate poisoning. Against soman poisoning the addition of obidoxime to HI-6 did not attenuate the efficacy of HI-6. The half-life of elimination and peak serum concentrations of HI-6 and obidoxime were not altered following administration of the combined injection. Reactivation of tabun-inhibited acetylcholinesterase was found consistently in the diaphragm but not in the brain. Using response surface methods it was possible to estimate the optimal therapy against soman and tabun poisoning (74.5 mg/kg HI-6 + 31.9 mg obidoxime against 1052 microns/kg obidoxime against 390 microns/kg challenge of soman).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholinesterase↗
PubMed1986

Effects of subchronic pyridostigmine pretreatment on the toxicity of soman.

The effect of subchronic pyridostigmine pretreatment on the toxicity of soman, in the absence of supporting therapy (atropine, oxime, and (or) anticonvulsant), as well as its effect on muscarinic cholinoceptor binding characteristics was assessed in the rat. Pretreatment with pyridostigmine by means of an implanted Alzet osmotic minipump for a 5-day total exposure dose of 12 mg/kg inhibited whole blood acetylcholinesterase activity by 73%. This pyridostigmine pretreatment lowered the soman LD50 from 104 micrograms/kg in control animals to 82 micrograms/kg. In addition, the time to onset of soman-induced convulsions in pyridostigmine pretreated animals was significantly (p less than 0.001) reduced. Pyridostigmine pretreatment produced no significant effect on muscarinic cholinoceptor binding in brain or ileum. Lower doses of pyridostigmine pretreatment inhibited acetylcholinesterase activity (65 and 25%); however, LD50 and time to onset of convulsions following soman (140 micrograms/kg) were not significantly different from controls.

Acetylcholinesterase↗
PubMed1986

Effect of soman (pinacolyl methylphosphonofluoridate) on the blood levels of corticosterone and adrenocorticotropin in mice.

Mice were poisoned by an extremely toxic organophosphate anticholinesterase soman (pinacolyl methylphosphonofluoridate), 50 or 100 micrograms/kg at 1000, and the serum concentrations of corticosterone were determined fluorometrically at 3-h intervals for at least 24 h. The lower soman dose (50 micrograms/kg) produced a modest increase in serum corticosterone concentrations but by 24 h the levels were not significantly different from control. Following the higher soman dose (100 micrograms/kg) the serum corticosterone levels were elevated significantly (p less than 0.05), for at least 27 h. However, ACTH concentrations were not elevated. It is possible that the elevated levels of corticosterone were due to a reduced metabolism and excretion of corticosterone resulting from the intense hypothermia, following soman poisoning which may change cardiac output and organ (liver and kidney) perfusion and not due to an enhanced release from the adrenal gland.

Adrenocorticotropic Hormone↗
PubMed1985

Hormonal consequences of organophosphate poisoning.

The hormonal changes were estimated after poisoning with an extremely toxic organophosphate, soman (pinacolyl methylphosphonofluoridate). Soman produced a significant (p less than or equal to 0.05) increase in serum corticosterone, thyroxine, and triidothyronine concentrations at 3, 6, and 9 hr after poisoning. However, by 22 hr the levels were not significantly different from control. Plasma ACTH levels were decreased at 3 hr after soman at 100 micrograms/kg but not after 287 micrograms/kg. Serum testosterone levels were decreased significantly (p less than or equal to 0.01) 6 and 9 hr after soman poisoning but had returned to control levels by 22 hr. Soman (100 micrograms/kg) produced an immunosuppressive response when administered at 24 hr after an antigen (sheep red blood cells). However, a similar response was obtained in adrenalectomized mice suggesting that some other mechanism other than elevated corticosterone was responsible for the immunosuppressive effect. Soman poisoning produced an intense hypothermia. It is possible that the hormonal changes noted after soman poisoning are due to a reduction in metabolism and excretion, a result of the hypothermia and not a direct action of soman.

Adrenocorticotropic Hormone↗
PubMed1984

Importance of aliesterase as a detoxification mechanism for soman (Pinacolyl methylphosphonofluoridate) in mice.

CBDP (2-/O-cresyl/4H:1:2-benzodioxaphosphorin-2-oxide) pretreatment produced a dramatic increase in the toxicity of soman in mice following the subcutaneous (s.c.) or intraperitoneal (i.p.) route of administration. This increase in soman toxicity was very highly correlated with inhibition of plasma aliesterase activity. Other enzymes (e.g. liver aliesterase and plasma cholinesterase) were inhibited by CBDP pretreatment; however, they did not appear to play a significant role in the potentiation of soman toxicity by CBDP. Liver aliesterase was not inhibited by doses of CBDP which produced significant increases in soman toxicity. Similarly, doses of Iso-OMPA, a selective inhibitor of pseudocholinesterase, which completely inhibited plasma cholinesterase, had no effect on soman toxicity. Pyridostigmine pretreatment which inhibited brain, diaphragm and plasma acetylcholinesterase 27, 57 and 60%, respectively, while not inhibiting plasma aliesterase, did not affect soman toxicity. The results of this study demonstrate that, in mice, plasma aliesterase is an extremely important detoxification route for soman.

Acetylcholinesterase↗
PubMed1984

Soman and sarin induce a long-lasting naloxone-reversible analgesia in mice.

Soman (50 micrograms/kg) and sarin (120 micrograms/kg), potent organophosphate anticholinesterase agents, produced an analgesic response in the mouse hotplate latency test. Naloxone antagonized but did not completely reverse the soman- and sarin-induced analgesia, whereas atropine antagonized completely the soman-and sarin-induced analgesia. Soman poisoning did not potentiate morphine-induced analgesia. It was simply an additive response. In survivors of soman (287 micrograms/kg) poisoning, the analgesia was more pronounced and was still apparent 96 hr after administration. This analgesia was completely antagonized by naloxone. Similar results were found in survivors of sarin (510 micrograms/kg) poisoning. The organophosphate-induced analgesia was not due to physical incapacitation as evidenced by performance on the accelerating rotorod. It is suggested that the organophosphate-induced analgesia is due to a combination of an increased concentration of acetylcholine due to inhibition of acetylcholinesterase combined with a reduced destruction of endogenous opioid-like substances due to organophosphate inhibition of proteases.

Analgesics↗
PubMed1984

Role of aliesterase in organophosphate poisoning.

Various doses of CBDP (2-(2- methylphenoxy )-4H-1,3,2- benzodioxaphosphorin -2-oxide), a metabolite of tri-o-cresyl phosphate, increased dramatically the acute toxicity of soman ( pinacolyl methylphosphonofluoridate ) in mice. CBDP (5 mg/kg; iv) reduced the soman LD50 value from 136 micrograms/kg in control to 6.95 micrograms/kg. The potentiation of soman toxicity following CBDP pretreatment appeared to be due primarily to inhibition of plasma aliesterase activity. Inhibition of liver aliesterase was not of primary importance in the potentiation of soman toxicity following CBDP pretreatment. In addition pretreatment with ISO-OMPA ( tetraisopropyl pyrophosphoramide ), a selective inhibitor of pseudocholinesterase, had no effect on the acute toxicity of soman. Similarly pretreatment of mice with pyridostigmine, a quaternary carbamate anticholinesterase which does not inhibit aliesterase , resulted in marked inhibition of diaphragm, plasma, and brain acetylcholinesterase had no effect on the acute toxicity of soman. Plasma aliesterase may be a depot for soman poisoning. The acute toxicity of soman by the ip, sc, and iv routes of administration was reduced following pretreatment of mice with phenobarbital (100 mg/kg) for 4 days. The reduced toxicity of soman following phenobarbital pretreatment was due to induction of liver aliesterase activity which subsequently resulted in an increase in plasma aliesterase activity. Thus more soman was probably bound to plasma aliesterase activity resulting in a reduction in acute toxicity of soman. Conversely pretreatment of mice with pentobarbital (70 mg/kg; ip) increased the toxicity of soman. This was probably the result of inhibition of plasma aliesterase by pentobarbital pretreatment combined with the central respiratory depression following pentobarbital administration. Following pentobarbital pretreatment soman inhibition of brain acetylcholinesterase was increased suggesting that plasma aliesterase inhibition alters the distribution of free soman in vivo. In summary, in mice plasma aliesterase appears to be an extremely important detoxification route for soman in vivo.

Acetylcholinesterase↗
PubMed1983

Antidote effect of sodium fluoride against organophosphate poisoning in mice.

Pretreatment of mice with atropine (17.4 mg/kg) + NaF (5 or 15 mg/kg) had a significant antidotal effect over atropine alone against the lethality produced by soman and sarin. Atropine + NaF (15 mg/kg) was effective against tabun, whereas the lower dose of NaF was not. An effect of NaF on organophosphate inhibited acetylcholinesterase could not account for the antidotal action of NaF. NaF had no effect on liver somanase activity but inhibited aliesterase activity. Aliesterase activity in NaF pretreated soman-poisoned mice was significantly (p less than 0.05) higher than in those receiving atropine alone. In CBDP-pretreated mice NaF did not significantly attenuate the toxicity of soman. It is hypothesized that the antidotal effect of NaF versus organophosphate poisoning is due to its antidesensitizing action at nicotinic receptors in the neuromuscular junction and/or sympathetic ganglia in addition to the proposed increased hydrolysis of sarin and direct detoxification of tabun.

Acetylcholinesterase↗
PubMed1983

Effect of pretreatment with sodium phenobarbital on the toxicity of soman in mice.

Pretreatment with sodium phenobarbital induces hepatic microsomal enzymes which are responsible for the metabolic breakdown of a large number of endogenous and exogenous chemical compounds. A previous study [K. P. DuBois and F. K. Kinoshita, Proc. Soc. exp. Biol. Med. 129, 699 (1968)] reported that phenobarbital pretreatment reduced the toxicity of various organophosphorus anticholinesterases; however, the exact mechanism for the increased detoxification was not investigated. In this study, the effect of phenobarbital pretreatment on the toxicity of soman was investigated. Male mice were injected daily for 4 days with sodium phenobarbital (100 mg/kg, i.p.) and used in the various experiments 24 hr after the last injection. Phenobarbital pretreatment produced a significant increase in liver weight and decreased the sodium pentobarbital (75 mg/kg, i.p.) induced sleep-time to 41 min compared to 141 min in controls. The lethality of soman was reduced following phenobarbital pretreatment. In control mice, the soman 24 hr LD50 values (microgram/kg) were 130, 393 and 42 following s.c., i.p. and i.v. administration, respectively, whereas in phenobarbital-pretreated mice the soman 24 hr LD50 values (microgram/kg) were 261, 746 and 63 following s.c., i.p. and i.v. administration respectively. Acetylcholinesterase activity was increased in the plasma (90%) but not in brain or diaphragm following phenobarbital pretreatment. Liver somanase activity was not affected. Liver aliesterase and serum aliesterase were both increased significantly following phenobarbital pretreatment. An increase in the amount of nonspecific binding sites for soman (esterases in liver and plasma) and not an increase in the metabolism of soman in vivo probably accounts for the protection afforded by phenobarbital pretreatment in mice.

Acetylcholinesterase↗