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At least 19 recordsLinked to original sources
PubMed1981

Gradual increase in the sensitivity of extraocular muscles to acetylcholine during topical treatment of rabbit eyes with isoflurophate.

During the course of four to 14 days of topical application of isoflurophate ointment to rabbit eyes, there was a gradual increase in the sensitivity to acetylcholine of the superior recti muscles of treated eyes in vitro in the absence but not in the presence of eserine. The development of increased sensitivity to acetylcholine was accelerated when isoflurophate was applied twice daily. This increased sensitivity to acetylcholine was maintained when, after two weeks of twice-daily isoflurophate treatment, the frequency of administration was decreased to two applications per week. Partial reversal of this effect occurred seven to 14 days after the last isoflurophate treatment.

Acetylcholine↗
PubMed1979

Separation and spectral properties of diisopropylphosphate, the major decomposition product of isoflurophate.

The reaction of water with isoflurophate to form diisopropylphosphate was examined and confirmed. Isolation of this decomposition product from an antiglaucoma drug formulation is described. A known reference compound was isolated from a commercial mixture also containing the monoisopropyl ester. The isolation, purification, and molecular spectroscopic and elemental confirmation of structure are described. IR, NMR, and mass spectra are included. Additionally, a GLC procedure and parameters used to identify diisopropylphosphate in a degraded peanut oil formulation of isofluorphate are reported. Reaction mixtures of this drug with water and sodium hydroxide were analyzed by GLC with the expected results.

Chromatography, Gas↗
PubMed1982

Mechanisms of recovery of brain acetylcholinesterase in rats during chronic intoxication by isoflurophate.

During chronic intoxication by diisopropyl fluorophosphate (Isoflurophate, DFP; s.c. treatment on alternate days - first dose of 1.1 mg/kg, subsequent doses of 0.7 mg/kg each until the 23rd day) a partial recovery of enzymatic activity was found at 24 h after each DFP administration. Relative to maximal AChE depression at 90 min, these rises were more pronounced in the soluble portion of the enzyme than in total enzyme preparation, i.e., that containing mainly membrane-bound AChE. Moreover, from the 2nd DFP administration on, there was a persistent increase of medium-molecular-weight forms both in soluble and in total AChE. The results suggest an important role of the soluble portion of AChE and of medium forms in the process of recovery of enzymatic activity.

Acetylcholinesterase↗
PubMed1994

Enhanced MPTP neurotoxicity after treatment with isoflurophate or cholinergic agonists.

Administration of the irreversible cholinesterase inhibitor isoflurophate (diisopropylfluorophosphate, DFP) before 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) enhanced the loss in tyrosine hydroxylase activity and dopamine and 3,4-dihydroxy-phenylacetic acid content in the striatum of mice in a dose-dependent manner. The effect of DFP on the MPTP-induced changes of dopaminergic markers was evident 30 days after initiating treatment, suggesting augmented neurotoxicity. Neurotoxicity was also enhanced by prior treatment with nicotine, carbachol or oxotremorine. We conclude that activation of either muscarinic or nicotinic receptors enhances the neurotoxicity of MPTP.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Sensitivity of blood-clotting factors and digestive enzymes to inhibition by organophosphorus pesticides.

Organophosphorus pesticide toxicology is normally evaluated in relation to inhibition of cholinesterases (acetyl and butyryl), neuropathy target esterase, and carboxylesterases, with less attention given to other physiologically important hydrolases. This study considers the relative organophosphate sensitivities of the aforementioned serine hydrolases compared with purified blood-clotting factors (thrombin, plasmin, and kallikrein) and digestive enzymes (alpha-chymotrypsin, trypsin, and elastase), assayed under similar conditions. Inhibitors that we examined are organophosphorus insecticides or their activated metabolites (paraoxon, chlorpyrifos oxon, and profenofos) and other toxicants (phenyl saligenin cyclic phosphonate and tribufos) for comparison with values that are found in the literature for the fluorophosphonates (isoflurophate and sarin). Thrombin is the most sensitive blood-clotting factor with IC-50 values of 19 to 160 microM for tribufos, the cyclic phosphonate, isoflurophate, and profenofos; plasmin and kallikrein are less affected (IC-50 >100 microM). Alpha-Chymotrypsin, trypsin, and elastase are most sensitive to the cyclic phosphonate (IC-50 1.3-15 microM) and less so to isoflurophate, sarin, and profenofos (IC-50 values from 3.6 to greater than 100 microM). The cholinesterases, carboxylesterase, and neuropathy target esterase are the most sensitive to inhibition with IC-50 values for the insecticides of less than 0.001 to 0.6, 0.002 to 0.009, and 0.15 to 100 microM, respectively. The generally low potency of these organophosphates for blood-clotting factors and digestive enzymes suggests that associated toxic effects are unlikely at sublethal doses.

Blood Coagulation Factors↗
PubMed2003

Rational design of alkylene-linked bis-pyridiniumaldoximes as improved acetylcholinesterase reactivators.

To improve the potency of 2-pralidoxime (2-PAM) for treating organophosphate poisoning, we dimerized 2-PAM and its analogs according to Wilson's pioneering work and the 3D structure of human acetylcholinesterase (hAChE) inactivated by isoflurophate. 1,7-Heptylene-bis-N,N'-syn-2-pyridiniumaldoxime, the most potent of the alkylene-linked dimeric reactivators, was readily synthesized using bistriflate and is 100 times more potent than 2-PAM in reactivating hAChE poisoned by isoflurophate. Experimental and computational studies confirm that 2-PAM in its biologically active form adopts the syn-I configuration. Further, they suggest that the improved performance of dimeric oximes is conferred by two-site binding with one oxime pointing toward the diisopropyl ester at the catalytic site of hAChE and the other anchored at the peripheral site. This type of binding may induce a conformational change in the acyl pocket loop which modulates the catalytic site via a domino effect.

Acetylcholinesterase↗
PubMed1990

Synthesis and release of acetylcholine by cultured bovine arterial endothelial cells.

Using cultured endothelial cells prepared from bovine carotid artery, and a specific radioimmunoassay for acetylcholine (ACh), the synthesis and release of ACh by vascular endothelial cells were investigated directly. ACh content in the culture medium after 24 h of incubation in the presence of isoflurophate, a nonspecific cholinesterase inhibitor, was about 16 times higher than that in endothelial cells, indicating that ACh synthesized inside the cells was released rapidly. The presence of ACh in the culture medium was further confirmed qualitatively using high-performance liquid chromatography with an electrocapture detection. These results represent the first direct evidence that endothelial cells can synthesize and release ACh, suggesting the possibility that ACh acts not only as a neurotransmitter but also as an autacoid under certain conditions.

Acetylcholine↗
PubMed1982

Development factors affecting brain acetylcholinesterase inhibition and recovery in DFP-treated rats.

The effect of a single dose of diisopropyl fluorophosphate (DFP; Isoflurophate, 1.1 mg/kg s.c.) administered to rats during pregnancy was evaluated by measuring postpartum maternal and newborn brain-soluble and total acetylcholinesterases (AChE) and their molecular forms at intervals of 1, 2, 3, 4 and 10 days between treatment and sacrifice. Subsequently, the effects of DFP were studied in 18-day-pregnant rats, fetuses and placentae at 90 min and 24 h after treatment. The inhibition of postpartum maternal enzymatic activity did not differ from that previously found in adult males, while inhibition was considerably less pronounced in newborns at all time intervals, with a nearly complete recovery already at 48 h after treatment. An even faster recovery of brain enzyme was observed in 18-day fetuses from DFP-treated mothers (24-hour interval between treatment and sacrifice). In this experiment, a comparable inhibition was observed at 90 min after treatment in the adult and the developing brain, excluding a major influence of disposition factors in the differential recovery phenomena. An experiment on weanling rats yielded intermediate results between those of newborn and those of adult animals. Finally, most data confirmed previous findings that the soluble portion of brain AChE and medium molecular weight enzyme forms may have special significance in the initial phases of recovery.

Age Factors↗