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Biomedical subjects

J G Clement

Publications and source records attributed to J G Clement.

104 records · Page 6Linked to original sources
PubMed1975

Inhibition of choline transport into human erythrocytes by choline mustard aziridinium ion.

Acetylcholine mustard aziridinium ion inhibited the transport of [3H]choline into human erythrocytes. Treatment of the erythrocytes with 1 X 10(-4) M tetraethylpyrophosphate prevented the inhibition of [3H]choline transport by acetylcholine mustard aziridinium ion. Hydrolyzed acetylcholine mustard aziridinium ion inhibited choline transport both in the presence and absence of 1 X 10(-4) M tetraethylpyrophosphate. The product of hydrolysis was equipotent with acetylcholine mustard in its ability to inhibit choline transport; incubation of this product with sodium thiosulfate prevented inhibition of choline transport thereby indicating the presence of an aziridinium ion. The hydrolysis product is likely to be choline mustard aziridinium ion. Results on the efflux of [3H]choline from erythrocytes in the presence of the proposed choline mustard aziridinium ion showed that the mustard moiety was transported into the red cells on the choline carrier. The rate of efflux of [3H]choline produced by choline mustard aziridinium ion was 55% of that produced by the same concentration of choline. It is concluded that acetylcholinesterase (EC 3.1.1.7) of red cells rapidly hydrolyzes acetylcholine mustard aziridinium ion to acetate and choline mustard aziridinium and the latter compound can act as a potent inhibitor of choline transport. This finding would indicate that the hemicholinium-like toxicity of acetylcholine mustard in the mouse is due to the formation of choline mustard aziridinium ion.

Biological Transport↗
PubMedDate not supplied

Effect of poisoning by soman (pinacolyl methylphosphonofluoridate) on the serum half-life of the cholinesterase reactivator HI-6 in mice.

The effect of fasting, atropine, and poisoning by an organophosphate anticholinesterase soman (pinacolyl methylphosphonofluoridate) on the pharmacokinetics of the acetylcholinesterase oxime reactivator HI-6 (CAS Reg. No. 34433-31-3; 1-[(4-(aminocarbonyl)pyridinio)methoxy)methyl)-2-(hydroxy imino)methyl) pyridinium dichloride) was investigated. Pharmacokinetic parameters (elimination half-life, volume of distribution, clearance rate) were determined for the following groups: (1) a 20 and 50 mg kg-1 dose of HI-6; (2) a 50 mg kg-1 dose of HI-6 after fasting for 18 h (water ad lib); (3) a 50 mg kg-1 dose of HI-6 at 0, 4, and 24 h after atropine (17.4 mg kg-1, i.p.) and soman (287 micrograms kg-1, s.c.); and (4) a 50 mg kg-1 dose of HI-6 at 0 and 4 h after soman (100 micrograms kg-1, s.c.). Fasting increased significantly (p less than 0.05) the elimination of half-life (t1/2) and tended to increase the volume of distribution (Vd) and decrease the clearance rate (CL). Following soman (287 micrograms kg-1) poisoning the t1/2 of HI-6 increased from 8.6 min to 21.6 min and the Vd increased to 0.731 kg-1. At the lower soman dose (100 micrograms kg-1) no significant effect on HI-6 pharmacokinetics was found. Atropine (17.4 mg kg-1: i.p.) pretreatment increased the t1/2 and CL while having no effect on the Vd. By 24 h the pharmacokinetic parameters of HI-6 in the various treatment groups were not significantly different from the control group. The changes in the pharmacokinetics of HI-6 following soman and atropine are probably the result of haemodynamic changes.

Animals↗
PubMedDate not supplied

Correlative light and backscattered electron microscopy of bone--part II: automated image analysis.

Detailed studies of biological phenomena often involve multiple microscopy and imaging modes and media. For bone biology, various forms of light and electron microscopy are used to study the microscopic structure of bone. Integrating information from the different sources is necessary to understand how different aspects of the bone structure interact. To accomplish this, methods were developed to prepare and image thin sections for correlative light microscopy (LM) and backscattered electron imaging in the scanning electron microscope (BSE-SEM). Images of the same fields of view may then be analyzed for degrees of relationships between specimen features not observed by LM or SEM alone. These methods are applied here to study possible associations between the degree of bone mineralization and pattern of collagen fiber orientation in the mid-shaft of the human femur. The "relational images" obtained allow us to examine the relationship between these two variables, both objectively and quantitatively.

Femur↗
PubMedDate not supplied

Differences in the toxicity of soman in various strains of mice.

The acute toxicity of soman was assessed in eight strains of mice (ALAS, CD-1, C57BL, CF1, CFW, C3H, DBA and BALB/c). In fasted animals the LD50 values for soman varied from 98 micrograms/kg in C57BL mice to 151 micrograms/kg in BALB/c mice. In general in non-fasted mice the soman LD50 was not significantly changed except in ALAS strain where the soman LD50 value increased significantly. The different sensitivities to soman poisoning among the various strains does not appear to be due totally to differences in level of brain acetylcholinesterase. Fasting had no significant effect on the activity of brain acetylcholinesterase and soman toxicity in CD -1 mice whereas, upon fasting ALAS strain mice for 18 hr, there was a 25% decrease in brain acetylcholinesterase which could explain their increased sensitivity to soman however, it is possible that other biochemical changes may also play a role.

Acetylcholinesterase↗
PubMedDate not supplied

Toxicology and pharmacology of bispyridium oximes--insight into the mechanism of action vs Soman poisoning in vivo.

HI-6 was the least toxic and the most efficacious oxime examined against Soman poisoning with a high safety ratio between 26-30. Reactivation of peripheral acetylcholinesterase following Soman poisoning was more important in the beneficial therapeutic action of HI-6 than reactivation of central acetylcholinesterase. HI-6 reactivated Sarin-inhibited but not Tabun-inhibited acetylcholinesterase both peripherally and centrally. HI-6 passes the blood brain barrier as evidenced by its reactivation centrally of Sarin-inhibited acetylcholinesterase. Soman-inhibited enzyme was not aged in vivo by 30 min. In vivo diaphragm acetylcholinesterase was inhibited to a greater extent by Soman, Sarin and Tabun than intercostal muscle acetylcholinesterase. In vitro diaphragm and intercostal muscle acetylcholinesterase had similar IC50 values for Soman. HI-6 has antimuscarinic and antinicotinic activity in addition to its previously reported ganglion blocking activity (Lundy and Tremblay, 1979). These additional pharmacological actions of HI-6 may play a role in the therapeutic action of HI-6 (at the higher concentrations). The results suggest that peripheral acetylcholinesterase in the rat diaphragm is the primary lesion in Soman poisoning. The beneficial action of HI-6 in rats versus Soman poisoning is due to reactivation of diaphragm acetylcholinesterase.

Acetylcholinesterase↗
PubMedDate not supplied

Effect of fasting on the acute toxicity of HI-6 and its efficacy in soman poisoned mice.

In rodents HI-6 is a very effective antidote of soman poisoning. After fasting, the IP LD50 value of HI-6 decreased from 660 mg/kg to 550 mg/kg. Fasting had no significant effect on the IV LD50 of HI-6. In fasted animals the ED50 for HI-6 (plus atropine) in soman toxicity decreased from 47.5 mg/kg to 14.8 mg/kg. Investigators should be aware of the nutritional status of the animals when comparing data between various laboratories.

Animals↗
PubMedDate not supplied

Efficacy of mono- and bis-pyridinium oximes versus soman, sarin and tabun poisoning in mice.

Various oximes (PAM, toxogonin, TMB-4, HS-6, HI-6, HGG-12, HGG-42) combined with atropine were compared as antidotes of soman, sarin and tabun poisoning in non-fasted CD-1 male mice. TMB-4 was the most toxic oxime with an i.p. LD50 value of 80 mg/kg and HI-6 was the least toxic oxime with an i.p. LD50 of 588 mg/kg. Upon comparing ED50 values, HGG-42 was the most effective oxime versus soman and tabun poisoning whereas, HI-6 was the most effective oxime versus sarin poisoning. Further research needs to be done to explain the distinct differences in efficacy of the oximes versus poisoning by soman, sarin or tabun.

Animals↗
PubMedDate not supplied

Histomorphogenesis of soman-induced encephalocardiomyopathy in Sprague-Dawley rats.

Although myocardial damage caused by soman has been previously reported, its relation to brain damage is unclear. In order to clarify this relationship, we examined the histomorphogenesis of central nervous system (CNS) and myocardial lesions in Sprague-Dawley rats, given atropine methylnitrate (20 mg/kg) and HI-6 (125 mg/kg) ip 10 min before a single injection of 0 or 130 micrograms soman/kg (sc) and sacrificed 45 min and 1.5 hr, 3 hr, 24 hr, and 72 hr later. Bilaterally symmetrical CNS damage began with vacuolation of the neuropil and was followed by astrocytic degeneration and neuronal necrosis culminating in liquefaction necrosis and focal hemorrhage. The cerebral cortex, limbic system, thalamus, and substantia nigra were common target sites. Repair in affected sites was characterized by capillary endothelial cell proliferation, microgliosis, and reversal of microvacuolation. Myocardial damage began with myocytolysis and contraction bands and evolved into coagulative myocytolysis and replacement fibrosis with a transient recruitment of acute inflammatory cells. The left ventricle, especially its free wall and papillary muscles, was consistently affected. There was good correlation among seizures, CNS damage, and myocardial lesions at all times following treatment. The results support the view that CNS lesions are associated with protracted seizure activity and provide evidence that myocardial damage is neurogenic.

Animals↗
PubMedDate not supplied

Early histopathologic and ultrastructural changes in the heart of Sprague-Dawley rats following administration of soman.

Male Sprague-Dawley rats were given atropine methylnitrate (20 mg/kg) and HI-6 (125 mg/kg) ip 10 min before a single injection of 130 micrograms soman/kg sc, and the heart was examined by light and electron microscopy 10, 25, 45, 90, and 180 min after the onset of seizures. Seizures appeared within 6-11 min after treatment. Control rats were given saline sc in place of soman. Early myocardial lesions consisting of hypercontraction and hyperextension of sarcomeres, focal myocytolysis, and contraction bands were detected in individual or groups of myocardial fibers. Hypercontraction was characterized by shortening of the sarcomere length, disappearance of the I and H bands, and thickening of the Z line. In contrast, hyperextended sarcomeres had thickened I and H bands. Myocytolysis was characterized by a progressively severe focal dissolution of myofilaments and edema of the affected sarcoplasmic area. Contraction bands appeared to result from the breakdown of markedly hypercontracted myofibril bundles. Due to the presence of a number of surviving myofilaments and the preservation of the sarcolemmal tube, distortion of the overall myocytic structure was minimal. Changes in the mitochondria and other intracellular organelles were also minimal and nonspecific. The close resemblance of morphologic findings to those induced by catecholamines supports the view that soman-induced myocardial damage is secondary to a treatment-related release of unphysiologic amounts of endogenous catecholamines.

Animals↗