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Biomedical subjects

J G Clement

Publications and source records attributed to J G Clement.

At least 19 recordsLinked to original sources
PubMed1992

Efficacy of HLö-7 and pyrimidoxime as antidotes of nerve agent poisoning in mice.

The toxicity and efficacy of two oximes, HLö-7 and pyrimidoxime, were evaluated in mice and compared to those obtained with HI-6. HLö-7 and pyrimidoxime produced 24 h LD50 values of 356 and 291 mg/kg (i.p.), respectively. In combination with atropine (17.4 mg/kg, i.p.), HLö-7 was a very efficient therapy against poisoning by 3 x LD50 dose of soman, sarin and GF and 2 x LD50 dose of tabun with ED50 values of 12.4, 0.31, 0.32 and 25.2 mg/kg, respectively. In contrast, pyrimidoxime was a relatively poor therapy which resulted in ED50 values of greater than 150, 5.88, 100 and 71 mg/kg against poisoning by soman, sarin, GF and tabun, respectively. HLö-7 produced significant (p less than 0.05) reactivation of phosphorylated acetylcholinesterase, in vivo, resulting in 47, 38, 27 and 10% reactivation of sarin, GF, soman and tabun inhibited mouse diaphragm acetylcholinesterase, respectively. HLö-7 also antagonized sarin-induced hypothermia in mice suggesting that it reactivated central acetylcholinesterase. The potential of HLö-7 as a replacement oxime for the treatment of nerve agent poisoning is discussed.

Animals↗
PubMed1992

Efficacy of various oximes against GF (cyclohexyl methylphosphonofluoridate) poisoning in mice.

The efficacy of oxime (HI-6, toxogonin or PAM Cl) therapy against GF (cyclohexyl methylphosphonofluoridate) poisoning was assessed in mice. It was found that the combinations of atropine and either toxogonin or HI-6 were effective therapies against GF poisoning. PAM therapy was ineffective. HI-6 was the only oxime which reactivated GF inhibited acetylcholinesterase. This might explain the reason why the HI-6 treated mice appeared to recover more quickly from the incapacitating effects following GF poisoning.

Animals↗
PubMed1992

Central activity of acetylcholinesterase oxime reactivators.

The ability of various oximes to antagonize the sarin-induced hypothermia and reactivate phosphorylated acetylcholinesterase was used as an indicator of the central activity of oximes. HI-6, but neither toxogonin nor PAM Cl, antagonized sarin-induced hypothermia and reactivated brain acetylcholinesterase, in particular hypothalamic acetylcholinesterase. The sarin-induced hypothermia appears to be a muscarinic cholinergic action since atropine was also an effective antagonist of sarin-induced hypothermia. Neither HI-6 nor toxogonin antagonized oxotremorine-induced hypothermia, indicating that these oximes do not possess central cholinolytic activity. The results demonstrated that HI-6 penetrated the blood-brain barrier in a sufficient concentration to produce a biochemical and physiological action against sarin poisoning.

Acetylcholinesterase↗
PubMed1992

Experimental calvarial growth disturbance by micro-plate and screw fixation.

A study was designed to help ascertain the effects of rigid internal fixation in the growing skull. Five piglets underwent plating of the left coronal suture at 3 weeks of age. At the time of surgery metal markers were placed to follow bone growth. Cephalometric radiographs, direct osteometry at sacrifice, gross pathological examination and specimen radiography revealed a localized disturbance of growth. There was a restriction of sutural displacement and appositional bone growth at the site of the plate. Local restriction of sutural growth was almost complete during the experimental period. There was an alteration to a 'mature' suture morphology, without synostosis, of the suture on the plated side not seen on the control side. A plagiocephalic pig was not produced nor was there an orbital deformity. A large local contour deformity developed and by the end of the experimental period the plate had become completely incorporated in bone. These effects were statistically significant as well as clinically significant. The clinical use of this type of fixation in reconstructive surgery of the infant craniofacial skeleton is questioned in light of the result.

Animals↗
PubMed1991

Soman and sarin inhibition of molecular forms of acetylcholinesterase in mice. Time course of recovery and reactivation by the oxime HI-6.

The in vivo sensitivity of the molecular forms of the enzyme acetylcholinesterase to inhibition by either soman or sarin, reactivation by HI-6 and the time course of recovery following inhibition by soman were investigated in mice. Administration of HI-6 (50 mg/kg, i.p.) immediately after soman (100 micrograms/kg, s.c.) or sarin (150 micrograms/kg, s.c.) resulted in an apparent selective reactivation of the 10S and 16S molecular forms of acetylcholinesterase and no reactivation of the 4S form of diaphragm acetylcholinesterase. The apparent selectivity of the reactivation of the molecular forms of the acetylcholinesterase was probably due to the fact that the 10S and 16S forms of acetylcholinesterase are located primarily extracellularly and the 4S form intracellularly. The HI-6 was restricted primarily to the extracellular compartment due to its quaternary, hydrophilic nature. If the administration of HI-6 was delayed until 60 min following soman (100 micrograms/kg, s.c.) injection, no reactivation of any of the molecular forms of acetylcholinesterase could be found in the diaphragm. The soman-inhibited acetylcholinesterase had probably aged and, thus, was not susceptible to reactivation by HI-6. The time course of recovery of the molecular forms in the diaphragm occurred rather quickly with the smaller 4S and 10S forms recovering to control levels faster than the larger 16S form. It took between 8 and 16 days for the 16S form to recover to normal. In the brain, hypothalamic acetylcholinesterase molecular forms such as the 4S recovered faster than the 10S form which had not recovered to control 16 days after soman administration; the 16S form of acetylcholinesterase was not detected in the brain.

Acetylcholinesterase↗
PubMed1991

Effect of a single dose of an acetylcholinesterase inhibitor on oxotremorine- and nicotine-induced hypothermia in mice.

Downregulation of cholinergic receptors is a consequence of subchronic exposure to an organophosphate anticholinesterase. The purpose of this investigation was to determine if there was a downregulation of the cholinergic receptors in mice following administration of a single dose of soman (pinacolyl methylphosphonofluoridate) or physostigmine. The change in the temporal response (mean minimum temperature and area under the curve) of core temperature following administration of either a muscarinic or nicotinic agonist such as oxotremorine (156 micrograms/kg, IP) or nicotine hydrogen tartrate (15 mg/kg, SC) was used as an indicator of downregulation of muscarinic or nicotinic receptors, respectively. Twenty-four h following soman (100 micrograms/kg, SC) administration, there was a significant decrease (p less than 0.05) in oxotremorine- but not nicotine-induced hypothermia. The significant differences in the mean minimum temperature and AUC were still present 4 days after exposure to the soman. Neither lower doses of the organophosphate anticholinesterase, soman (50 and 70 micrograms/kg), nor the carbamate anticholinesterase, physostigmine (500 micrograms/kg), produced a significant change in either oxotremorine- or nicotine-induced hypothermia. The results of this study suggest that receptor downregulation observed after subchronic administration of soman is also evident following administration of a single, sublethal dose of an organophosphate anticholinesterase, soman, but not after administration of a carbamate anticholinesterase, physostigmine. The in vivo assessment of the muscarinic receptor using oxotremorine hypothermia may be a sensitive indicator of the functionality of the drug-receptor coupling and indicate a physiological consequence of receptor downregulation.

Animals↗
PubMed1991

Hypothermia: limited tolerance to repeated soman administration and cross-tolerance to oxotremorine.

The effect of repeated administration of the organophosphate anticholinesterases, soman (pinacolyl methylphosphonofluoridate) and DFP (diisopropylfluorophosphate) on core temperature was investigated in mice. Mice were implanted with telemetry transmitters for the monitoring of core temperature. Following repeated administration of soman (3-10 injections), tolerance (as defined by a decrease in the organophosphate-induced hypothermia upon subsequent administration) to the organophosphate-induced hypothermia was evident after the 5th injection; however, there was cross-tolerance to oxotremorine hypothermia as early as after the 3rd injection of soman. Following repeated administration of DFP, there was no tolerance to the DFP-induced hypothermia following 5 injections, whereas cross-tolerance to oxotremorine was evident following the 5th injection. The organophosphate-induced hypothermia may have another component which contributes to the response. It is proposed that the cross-tolerance to oxotremorine hypothermia after subchronic administration of an anticholinesterase is representative of the functionality of muscarinic cholinergic receptor coupling.

Acetylcholinesterase↗
PubMed1990

Effects of soman poisoning on hematology and coagulation parameters and serum biochemistry in rabbits.

The effects of soman poisoning on hematological (counts of red blood cells (RBC), white blood cells (WBC), and platelets and measurement of hematocrit) and coagulation parameters (prothrombin time, activated partial thromboplastin time, thrombin time and concentrations of fibrinogen, factor V, factor VII, and factor XI) and serum biochemistry (concentration of albumin, protein, calcium, cholesterol, triglycerides, blood urea nitrogen (BUN), magnesium, and creatinine and activities of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, cholinesterase, creatinine phosphokinase (CPK), hydroxybutyrate dehydrogenase, and amylase) were determined at 1, 2, 4, 24, and 48 hours after poisoning of rabbits. There were significant (p less than 0.05) decreases in the RBC counts in all treatment groups that were measured initially at 4 hours and were reflected by parallel decreases in the hematocrit values. These changes were probably due to an increase in the hemolysis of the RBC rather than a decrease in the production of RBC. There were minor changes in the coagulation parameters. Generally, the fibrinogen content increased. The activated partial thromboplastin time decreased significantly (p less than 0.05) 24 and 48 hours after soman (50 micrograms/kg) poisoning. Blood cholinesterase values were significantly reduced in all treatment groups at all time periods. The CPK activity was increased after 4 and 24 hours in the 20 and 50 micrograms/kg soman groups. There were minor changes in the other biochemistry values, but none that showed a dose-response relationship; thus, they were considered to be of limited significance with regard to the toxic manifestations of soman exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Pharmacological actions of HS-6, an oxime, on the neuromuscular junction.

The effect of HS-6 [1-(2-hydroxyiminomethylpyridinium)-1-(3-carboxamidopyridinium)-dimethyl ether] on neuromuscular (NM) transmission was investigated using chick biventer cervicis (CBC), rat diaphragm (RD) and guinea pig ileum longitudinal muscle strip (GPLS) preparations. In the CBC preparation HS-6 did not cause a contraction, whereas it produced a dose-related contraction of the GPLS preparation. HS-6 produced a hemicholinium-like NM blockade in the CBC and RD preparations. This was supported by the fact that HS-6 inhibited choline uptake in erythrocytes. HS-6 inhibited the contractions of various nicotinic agonists in the CBC preparation and augmented the acetycholine contractions. The latter was due to AChE inhibition produced by HS-6.

Animals↗
PubMed1979

Echogenic fluid: a pitfall in the ultrasonographic diagnosis of cystic lesions.

Although it is well known that biliary sludge can produce fine diffuse echoes within the gallbladder, it is less commonly appreciated that other cystic structures may contain echogenic fluid and therefore be mistaken sonographically for solid lesions. In this article three cases of splenic cysts and one case each of pyrometrocolpos, hydroureter, and pyonephrosis presented with diffuse fine echoes in the fluid. Three of these cases were misinterpreted as a result of this echogenic appearance. These cases serve to emphasize the need for awareness of the echogenicity of some types of fluid and the value of other signs of cystic lesions besides absence of internal echoes.

Adult↗
PubMed1978

Effect of ethanol, pentobarbital and morphine on the toxicity of hemicholinium-3 and d-tubocurarine in mice.

Pretreatment of mice with either ethanol, pentobarbital or morphine protected against the lethal effects of hemicholinium-3 (HC-3) but not curare. The protective action of these compounds was not due to an induced release of corticosteroids in vivo since administration of prednisolone did not protect against HC-3 toxicity. The protective action of morphine was reversed by Nalline hydrochloride. The results suggest that the site of the protective action of ethanol, pentobarbital and morphine and the site of action of the lethal respiratory depression by HC-3 are central in origin.

Animals↗
PubMed1975

Presynaptic effect of the aziridinium ion of acetylcholine mustard (methyl-2-acetoxyethyl-2'-chloroethylamine) on the phrenic nerve--rat diaphragm preparation.

The rat diaphragm has been used to investigate the neuromuscular blocking action of acetylcholine mustard which yields a potent nicotinic agonist, an aziridinium ion, in aqueous medium. Evidence was obtained that the acetylcholine mustard aziridinium ion impaired neuromuscular activity when the phrenic nerve was stimulated and that the ion did not directly inhibit muscle contraction. Impairment of neuromuscular activity was characterized by a latent period and depended both on the concentration of aziridinium ion and the frequency of stimulation of the phrenic nerve. Elevated concentrations of Ca-2+ and choline changed the response of the rat diaphragm to the aziridinium ion, the former increasing the rate of development of neuromuscular block and the latter protecting against neuromuscular block. These results indicated that the aziridinium ion may act either at the site of choline uptake or have an effect on acetylcholine synthesis in the nerve ending and that impairment of neuromuscular transmission in the rat diaphragm involved the availability of acetylcholine. Similar results were obtained with acetylcholine mustard aziridinium ion subjected to alkaline hydrolysis. This substance is thought to be choline mustard aziridinium ion. Although difficult to prove with the rat diaphragm it is possible that acetylcholinesterase of this preparation could hydrolyze acetylcholine mustard aziridinium ion at the neurotransmitter site and the resultant choline mustard aziridinium ion would interfere with the uptake of choline and eventually prevent neuromuscular transmission. This hemicholinium-like hypothesis for the mechanism of action of choline mustard aziridinium ion is compatible with reported date for toxicity of acetylcholine mustard aziridinium ion in the mouse.

Acetylcholine↗