Octamethyl Pyrophosphoramide Research Articles

Biological effects of the metabolites of dimethyl sulfoxide.

In summary, the effects of dimethyl sulfoxide (DMSO) and its metabolites, dimethyl sulfone (DMSO2) and dimethyl sulfide (DMS), were studied in five selected systems in rats and mice. DMSO enhanced the taurine excretion and the lethality produced by such aromatic hydrocarbons as benzene and chlorobenzene in rats. In mice, DMSO decreased the toxicity such cholinesterase inhibitors as paraoxon and octamethyl pyrophosphoramide. DMSO also lowered the body temperture of rats and reduced the motor activity of mice. Although DMSO2, the major metabolite of DMSO, was not effective in increasing the lethality of solvent hydrocarbons, it seemed to be quite as effective with respect to the other effects. DMS, although quite potent with respect to lowering body temperature and reducing motor activity, was relatively ineffective otherwise. Thus each of the metabolites has a spectrum of activity different from the parent compound; DMSO has the widest spectrum and DMS the narrowest. It remains to be determined whether the therapeutic effects of DMSO are related to the experimental effects reported above in animals, and whether DMSO2 and DMS may share any of the therapeutic effects of DMSO.

Increased lethal effects of acutely administered anticholinesterases in female rats prefed with similar agents

Increased sensitivity to acutely injected O,O-dimethyl-1-hydroxy-2,2,2-trichloroethylphosphonate (trichlorfon) and physostigmine was observed in rats prefed 50 ppm of either octamethylpyrophosphoramide (OMPA) or parathion daily for 40 days. Differences were found in cholinesterase activities in brain, red cells, and plasma between OMPA- and parathion-treated rats sacrificed at 40 days. Increases in the acute lethal effects of physostigmine and trichlorfon were observed in remaining OMPA- and parathion-prefed rats injected at the time of enzyme assay.

The reaction of vanadium and titanium (IV) chlorides with some ligands containing PO or AsO groups

Vanadium (IV) chloride forms 1:1 and 1:2 adducts when treated with hexamethylphosphoramide (HMPA) but a 1:1 compound only is obtained with octamethylpyrophosphoramide (OMPA). 1:2 compounds are formed with triphenylphosphine oxide and triphenylarsine oxide whereas triethyl and triphenyl phosphates reduce vanadium (IV) to give compounds of the type VCl 3·2 ligand. No reduction of titanium (IV) chloride occurs with these last two ligands, the compounds TiCl 4[triethyl phosphate] 2·0 and TiCl 4[triphenyl phosphate] 1·0 being isolated. The i.r. and visible spectra of the compounds prepared are recorded and structures suggested on the basis of these and other physical measurements.

Metal complexes of ethyl dimethylamidopyrophosphates

Metal ion complexes of asym-diethyltetramethyldiami- do-pyrophosphate (ASM) and ethl hexamethyltria- midopyrophosphate (MONE) have been prepared. Complexes of tetraethyl pyrophosphate (TEPP) are very difficult to isolate. Thus far, only an adduct of TEPP with antimony pentachloride has been isolated. The coordinating ability of ASYM, MONE, and TEPP is compared with that of octamethylpyrophosphoramide (OMPA) and sym-diethyl tetramethyl- diamidopyrophosphate (SYM). The order of coordinating ability is OMPA>MONE>SYM>ASYM>TEPP.

1870. Testing organophosphates in man: Rider, J. A., Moeller, H. C., Puletti, E. J. & Swader, Joyce I. (1969). Toxicity of parathion, systox, octamethyl pyrophosphoramide, and methyl parathion in man. Toxic. appl. Pharmac.14, 603

1870. Testing organophosphates in man: Rider, J. A., Moeller, H. C., Puletti, E. J. & Swader, Joyce I. (1969). Toxicity of parathion, systox, octamethyl pyrophosphoramide, and methyl parathion in man. Toxic. appl. Pharmac.14, 603

Altered sensitivity to drugs following repeated injections of a cholinesterase inhibitor to rats

The chronic administration of O,O-diethyl S-2-(ethylthio)ethyl phosphorodithioate (Di-Syston) is accompanied by the development of tolerance to the cholinomimetic effects of this compound. Rats which had developed tolerance to Di-Syston were found to be less susceptible to the subacute lethal action of octamethyl pyrophosphoramide (OMPA) than control rats. The sensitivity of Di-Syston-tolerant rats to the subacute lethal action of parathion, however, was unchanged. Di-Syston tolerant rats were also found to be resistant to the acute lethal action of oxotremorine, but the sensitivity of these rats to the acute lethal action of d-tubocurarine, decamethonium, and OMPA was increased. The chronic administration of Di-Syston appears to produce some type of change in rats which reduces susceptibility to certain cholinomimetic drugs. The results with d-tubocurarine and decamethonium would suggest that, at the same time, the susceptibility to neuromuscular blocking drugs is increased.

Factors affecting the toxicity and metabolism of OMPA (octamethylpyrophosphoramide) in rats.

Octamethylpyrophosphoramide (OMPA) is a potent inhibitor of cholinesterase in vivo. However, OMPA itself is a very weak inhibitor, but it is converted to a potent inhibitor following oxidation by liver microsomes (1-4). In a pervious paper it is reported that the administration of thiopental or phenaglycodol markedly increased the toxicity of OMPA in female rats (5). Since the joint administration of ethionine with thiopental or phenaglycodol completely blocked the effect of thiopental or phenaglycodol, it was postulated that the induction of microsomal enzyme which activates the metabolism of OMPA was involved in the increased toxicity after thiopental or phenaglycodol treatment. In the present investigation, the effect of phenobarbital and methylcholanthrene on the toxicity and metabolism of OMPA in female and male rats were studied to confirm this postulation. Phenobarbital and methylcholanthrene are well known inducers of drug-metabolizing enzymes of liver microsomes (6-8). However, the administration of both drugs likely give different effects on the microsomal enzymes (9-11). The typical difference were also evidenced in the present works. In addition the marked sex difference was observed on the metabolism of many drugs by liver microsomes, and the metabolism of OMPA in male rats was much faster than that in female rats (2, 12-16). In the present studies the marked sex difference was also observed in the effect of phenobarbital and methylcholanthrene on the metabolism and toxictity of OMPA. These results may offer a typical example for the role of the metabolism of drugs by liver microsomes for the determination of drug toxicity.

The Anticholinesterase Activity of the Babesicidal Agents Quinuronium and Amicarbalide and the Influence of Pyridine 2-Aldoxime Methiodide

SUMMARY The piroplasmocidal agents quinuronium and amicarbalide were investigated for anticholinesterase activity in the blood of 9 species in vitro. Quinuronium was shown to be a potent inhibitor of circulating cholinesterases in all the species, whereas amicarbalide was much less active. In the sheep in vivo, quinuronium caused about 40% inhibition of cholinesterase and recovery of activity took place over a period of 24 to 48 hr. Eserine produced profound but transient inhibition and amicarbalide had a very small effect. Pyridine 2-aldoxime methiodide (2-PAM) failed to protect the enzyme from inhibition by quinuronium or eserine but temporarily relieved the inhibition produced by the organo-phosphorus compound octamethylpyrophosphoramide (OMPA). During all experiments in vivo in sheep, atropinisation (1 mg. per kg.) was used, and it was concluded that atropine provided the best antidote to quinuronium poisoning and the 2-PAM did not appear to alleviate circulating cholinesterase activity which had been inhibited by quinuronium.

Adaptation to octamethyl pyrophosphoramide in rats

Some of the characteristics of the adaptation of rats to the organophosphate anticholinesterase agent, octamethyl pyrophosphoramide (OMPA), were studied. Evidence was obtained that the mechanism of the adaptation to OMPA is not based on a change in the ability of the liver to activate it or to destroy its activated form. While there was some indication of an increased production of cholinesterase in adapted rats, the adaptation could not be explained definitely on this basis. The process of adaptation to OMPA was related to the rate at which cholinesterase levels are depressed. Rats survived when diaphragm cholinesterase was gradually lowered over a period of 20 days to 20% of the normal level, but died when the enzyme level was depressed to this extent in 6 days. In rats adapted to OMPA, interruption of the daily injections was followed by recovery of normal sensitivity to OMPA after 12 days. Recovery to normal sensitivity was parallel with a recovery of the diaphragm cholinesterase level to near normal. Rats adapted to Di-Syston showed a cross-resistance to OMPA, but not to parathion. Animals adapted to OMPA were more sensitive than normal animals to single large doses of OMPA or of acetylcholine. The adaptation observed appears to be specifically an adaptation to a subacute treatment schedule of daily doses of OMPA and not to single toxic doses.

Effect of chlorcyclizine on the toxicity and metabolism of octamethyl pyrophosphoramide

1. 1. Rats and mice were protected from the lethal effect of OMPA by pretreatment with a single dose of chlorcyclizine administered shortly before OMPA. 2. 2. A single dose of chlorcyclizine also prolonged hexabarbital sleeping time in both species. 3. 3. In vitro, chlorcyclizine inhibited the transformation of OMPA to the toxic metabolite, which is a potent cholinesterase inhibitor. 4. 4. The administration of chlorcyclizine to mice twice a day for 3 days did not increase or decrease the toxicity of OMPA although hexobarbital sleeping time was decreased. 5. 5. Similar treatment of rats with chlorcyclizine resulted in a decreased OMPA toxicity although hexobarbital sleeping time was unaltered. 6. 6. Triacetin esterase activity of rat liver was not affected by repeated chlorcyclizine administration although the activity of this enzyme in plasma was slightly decreased. 7. 7. Treatment of rats for 3 days with chlorcyclizine resulted in inhibition of OMPA activation by the liver. 8. 8. Evidence is presented which indicates that the active metabolite of OMPA is not destroyed by liver enzymes.

Variation in the activity of liver microsomal drug-metabolizing enzymes in rats in relation to the age

The variation in the activity of the microsomal drug-metabolizing enzymes in rats in relation to age was studied. The systems used were the in-vitro metabolism of hexobarbital, pentobarbital, meprobamate, carisoprodol and strychnine, the in-vivo metabolism of pentobarbital, meprobamate and carisoprodol and the duration of pentobarbital hypnosis and carisoprodol paralysis and the toxicity of strychnine and OMPA (Octamethylpyrophosphoramide). New-born rats showed only a very low metabolic activity, but this increased progressively until 30 days after which it gradually decreased with aging. In the metabolisms in vitro, 30-day-old rats showed about 2.7, 2.2, 1.7 and 1.5 times higher activity than those of 250, 150, 100 and 60 days old, respectively. Similar, though smaller, differences were observed in vivo. The duration of pentobarbital hypnosis, carisoprodol paralysis and strychnine toxicity was almost the same in immature (30 days old) and adult rats (60–150 days old). Possibly, the immature have a higher sensitivity to the drugs than the adult rats, but this is overshadowed by the higher metabolic activity in the immature rats. The possible mechanism for the marked difference in the activity in vitro of the drug-metabolizing enzymes among the differently aged rats is discussed in connection with the variation of in-vivo metabolism and activity of microsomal TPNH oxidase.

Treatment of anticholinesterase intoxication with oximes; use in normal subjects and in patients with myasthenia gravis.

Intoxication by anticholinesterase compounds may occur in normal subjects after accidental exposure to organophosphorus insecticides (e. g., parathion 1 and tetraethylpyrophosphate [TEPP] 2 ) and chemical warfare agents (e. g., sarin, one of the nerve gases, isopropyl methyl phosphonofluoridate 3 ). Similar intoxication may occur as a result of overtreatment of patients with myasthenia gravis with anticholinesterase medication, whether organophosphorus (TEPP or octamethyl pyrophosphoramide [OMPA]) or quaternary ammonium (neostigmine [Prostigmin], bis-neostigmine [BC-40], pyridostigmine [Mestinon], bis-pyridostigmine [hexamarium, BC-51], or ambenomium [Mytelase] ). 4 These compounds inhibit cholinesterase enzymes throughout the body, resulting in local accumulation of acetylcholine, which produces increased activity of smooth muscle and secretory glands ( manifested by nausea, vomiting, diarrhea, sweating, and increased salivary and bronchial secretion), bradycardia, central nervous system symptoms, muscular weakness, and fasciculations in normal subjects, 3 and increased strength which may be followed by weakness in patients with myasthenia gravis. 4a In the management of the latter disease,

Use of Parasympathetic Stimulation in the Production of Bloody Diarrhea in Dogs, with Reference to the Role of Red Cell and Colon Cholinesterase

Summary 1.Postganglionic celiac, superior and inferior mesenteric sympathectomy was associated with chronic, nonbloody diarrhea in 10 dogs. 2.Daily intramuscular injections of Mecholyl in oil (0.5 to 4.0 mg. per kg. per day) in 8 dogs led to bloody diarrhea in 3. In 2 of these the dose was 2.5 to 4.0 mg. per kg.; in the third, 1.0 mg. per kg. was given. 3.In contrast, acute and massive bloody diarrhea was produced in 4 out of 5 of these animals by administration of 0.5 to 1.5 mg. per kg. of Mecholyl following reduction of red blood cell and colon cholinesterase to 26 per cent and 30 per cent or less of control values, respectively, by means of oral administration of 1.0 mg. per kg. of octamethylpyrophosphoramide (OMPA) over a period of many weeks. Of importance, OMPA per se did not lead to bleeding, except in 1 animal which received 4 mg. per kg. for five days. 4.Explanation for this effect may lie in the results of several colon motility experiments which demonstrated that inhibition of colon tissue cholinesterase (Che potentiates contractile effect of a parasympathomimetic agent, although threshold dosage remains unaltered. 5.The significance of these findings is discussed in the light of the role of autonomic influences upon the colon in human beings, with reference to idiopathic ulcerative colitis.

The long-acting anticholinesterase drugs in the management of myasthenia gravis

1. 1. The published studies on the treatment of myasthenia gravis with long-acting anticholinesterase drugs—di-isopropylfluorophosphate (DFP), hexaethyltetraphosphate (HETP), tetraethylpyrophosphate (TEPP), and octamethyl pyrophosphoramide (OMPA)—have been reviewed and correlated with studies on 21 patients treated by us with OMPA. 2. 2. The data indicate that OMPA possesses most of the desirable qualities which could be expected of long-acting anticholinesterase compound for the use in the management of myasthenia gravis: it is stable in aqueous solution; it is well absorbed when administered orally; it is highly effective in producing “irreversible” inhibition of ChE; finally, it is essentially free of actions on the central nervous system. The data also suggest that it is improbable that any other compound whose effects are due to more or less “irreversible” inhibition of ChE will prove significantly superior to OMPA in the management of patients with myasthenia gravis. 3. 3. Long-acting anti-ChE agents should not be administered to patients with myasthenia gravis of progressively increasing severity and should be given only with great caution to patients with stable but severe disease. 4. 4. Octamethyl pyrophosphoramide (OMPA) is an excellent agent for the treatment of the patient with only moderately severe and stable myasthenia gravis. By its use some patients can be transformed from semi-invalidism to essentially normal activity. 5. 5. Experience with the long-acting anticholinesterase drugs demonstrates that even maximal inhibition of peripheral ChE may fail to control myasthenic weakness. Adequate management of severe or progressive instances of the disease must await a better understanding of its pathologic physiology.

Experiments with a Systemic Insecticide for the Control of Schoenobius incertulas (Wlk.) (Lepidoptera, Pyralidae), A Stem Borer of Paddy in West Bengal

SummaryExperiments were carried out in West Bengal to ascertain whether the Paddy Stem Borer, Schoenobius incertulas (Wlk.) could be controlled by “Tetrax” 1, a systemic insecticide containing technical schradan equivalent to approximately 42 per cent, octamethyl pyrophosphoramide + approximately 25 per cent, triphosphoric acid pentadimethylamide.In a preliminary experiment, treatment had little effect on the damage caused by the borer but the yield of grain was higher from a treated plot than from a control plot.A further experiment was carried out, the following year, in which the seed was soaked in a 0·1 per cent, water solution of “Tetrax” 1 for eight hours before sowing in the seed beds. The seedlings were lifted about 2½ months later and steeped in 0·1 per cent. “Tetrax” 1 for eight hours before transplanting into two plots, each 32 ft. × 32 ft. About three weeks later the plants were sprayed with a solution of the same strength. Two plots of similar size, in which the paddy had received no treatment, were maintained as controls.Again there was very little difference, between the treated and untreated plots, in the damage caused to the ear heads by the pest, but the treated plots produced 108·68 lb. of grain as against 77·27 lb. for the untreated plots. The increase was largely due to an increase in the number of ear heads per plant.The incidence of the borer was too low in both experiments to determine whether “Tetrax” 1 exercised any appreciable control, but the treatment did give rise to a higher yield of grain under the conditions of the experiments.

A specific antidote against lethal alkyl phosphate intoxication. II. Antidotal properties

A recently synthesized compound, pyridine-2-aldoxime methiodide (PAM), which is a powerful reactivator of acetylcholinesterase inhibited by certain alkyl phosphates [diethyl- p-nitrophenyl phosphate (paraoxon) and diisopropyl fluorophosphate (DFP)], has been tested on white mice as to its properties as an antidote against a lethal dose of these toxic agents. The following results were obtained: 1. 1. Before using PAM as an antidote, its toxicity was determined. The amount of PAM which kills 50% of the mice injected ( LD 50) is 137 mg./kg. The minimal lethal dose observed is 100 mg./kg.; the sure lethal dose is about 200 mg./kg. 2. 2. PAM has no atropine-like action as has been shown by the failure to antagonize the effects of acetylcholine on the blood pressure of the eviscerated cat. 3. 3. An amount of 30 mg./kg. of PAM injected intraperitoneally protected 100 % of the animals against a sure lethal dose of either paraoxon ( LD 100 = 0.9 mg./kg.) or DFP (5 mg./kg.) injected subcutaneously. 4. 4. In combination with 10 mg./kg. of atropine, PAM (50 mg./kg.) protected 100 % of the animals against 10 mg./kg. of paraoxon, which is about 15 times the LD 50 (0.7 mg./kg.). 5. 5. In combination with atropine, PAM provided 100% protection against 20 mg./kg. DFP (5 times LD 50). But even when 75 mg./kg. DFP was injected, still four out of ten animals survived with PAM and atropine. 6. 6. PAM provides apparently little or no protection against octamethylpyrophosphoramide (OMPA). 7. 7. Since the phosphoryl enzyme derived from OMPA is not readily reactivated by PAM, the lack of protection emphasizes the direct relationship between antidote properties and the reactivation of the enzyme. 8. 8. The data show that a specific and efficient antidote has been obtained against certain alkyl phosphates by a reactivator of acetylcholinesterase. Since other esterases are much less readily reactivated by PAM, the observations support the view that the high toxicity of alkyl phosphates must be attributed specifically to the inhibition of acetylcholinesterase.

The manifestations and treatment of poisoning due to nerve gas and other organic phosphate anticholinesterase compounds.

THE NERVE gases are a group of highly toxic organic esters of phosphoric acid derivatives which have physiologic effects attributable to the inhibition of cholinesterase enzymes. The effects resemble those produced by physostigmine and neostigmine (Prostigmin) but are more intense and more prolonged. The nerve gases are among the most toxic of the chemical warfare agents, and they are the most adaptable to long-range attack, as upon civilian populations. 1 A number of related but somewhat less toxic organic phosphate anticholinesterase compounds have proved to be useful in medicine and in agriculture. Diisoprophyl fluorophosphate (DFP) has been studied in detail* and has been employed as a therapeutic agent in the management of abdominal distention,† urinary retention, and glaucoma. 6 Tetraethylpyrophosphate (TEPP) 7 and octamethyl pyrophosphoramide (OMPA) 8 proved to be of some value in the management of myasthenia gravis, but they have been replaced by less potent anticholinesterase compounds. Parathion, bis-(monoisopropylamino)-fluorophosphine

Conversion of schradan and parathion by an enzyme system of rat liver.

SCHRADAN (octamethyl pyrophosphoramide) and parathion (OO-diethyl O p-nitrophenyl phosphorothionate) are converted by insects or mammals into inhibitors of cholinesterase. In mammals the liver is responsible for the metabolism of both compounds1 and the conversion appears to be an oxidative one.

BELLADONNA DRUGS IN CHOLINERGIC POISONING DURING TREATMENT OF MYASTHENIA GRAVIS

To the Editor. —Since the introduction of neostigmine in 1934 by Mary Walker in the treatment of myasthenia gravis, various other anticholinesterase (cholinergic) drugs have been used in the treatment of this disease with varying success. Some of these, such as diisopropyl fluorophosphate (DFP), tetraethyl pyrophosphate (TEP), and octamethyl pyrophosphoramide (OMPA), produced long depression of the serum cholinesterase, depression lasting for from several days to several weeks. The most successful for treatment of myasthenia was octamethyl pyrophosphoramide, but this drug is no longer available because of the tremendous difficulties and dangers in its manufacture. With all of these drugs, as well as with neostigmine, the side-effects of intense stimulation of the gastrointestinal tract made it difficult to obtain a good therapeutic result in some patients unless belladonna derivatives were given with each dose of the anticholinesterase compound. When this was done, the gastrointestinal effects disappeared, but at the same time

Studies in myasthenia gravis: present status of therapy with octamethyl pyrophosphoramide (OMPA).

Excerpt In 1935 neostigmine1was introduced as an agent for the treatment of myasthenia gravis. It is still the drug of choice but, because of the frequency of dosage and the development of refracto...