A method for the simultaneous quantitation of metrifonate (0,0-dimethyl-(1-hydroxy-2,2,2-trichloroethyl)-phosphonate) and dichlorvos (2,2-dichlorovinyl dimethyl phosphate, DDVP) in human blood has been worked out. It is based upon multiple labelling of the compounds with deuterium and gas phase analysis using the mass spectrometer as a selective detector. The amount of DDVP in plasma is about 1% of the amount of metrifonate. In erythrocytes the corresponding amount of DDVP is 0.5% or less of metrifonate. Both compounds reach peak levels in blood within two hours after oral dosing and are detectable for at least eight hours. Cholinesterase activity in plasma reaches zero levels within 15 min. and remains inhibited for more than eight hours. Red blood cell cholinesterase is inhibited only 60-80%. According to kinetic calculations, clearance of metrifonate occurs primarily via dichlorvos. If dichlorvos is the only active component, which in all likelihood it is, it's slow release may be important in the schistosomicidal effect. Clinical data in seven metrifonate treated patients revealed that mild vertigo subsiding in a few hours was the most common side effect.

Adolescent↗

PubMed1980

Prolegomena to Seveso. Ecclesiastes I 18.

Explore the source record for details and available documents.

Accidents, Occupational↗

PubMed1980

Concentration of serotonin metabolites in the cerebrospinal fluid from alcoholics before and during disulfiram therapy.

The levels of 5-hydroxytryptophol and 5-hydroxyindoleacetic acid were measured in the cerebrospinal fluid before and after one week of disulfiram treatment (400 mg/day) from ten male hospitalized alcoholic patients. The disulfiram treatment induced elevated (P less than 0.001) levels of 5-hydroxytryptophol. The levels were higher than in a control group, both before (P less than 0.01) and after (P less than 0.001) the treatment. No effects on the levels of 5-hydroxyindoleacetic acid were noted. The results indicate an altered serotonin metabolism in alcoholics, which is further potentiated by disulfiram treatment.

Alcoholism↗

PubMed1980

Plasma levels of metrifonate and dichlorvos during treatment of schistosomiasis with bilarcil.

Metrifonate (0,0-dimethyl-[1-hydroxy-2,2,2-trichloroethyl]-phosphonate), and its rearrangement product dichlorvos (2,2-dichlorovinyl dimethyl phosphate) (DDVP), were studied in plasma from two patients with schistosomiasis who were treated with Bilarcil. A mass fragmentographic technique was used. Isotopic variants of the substances were used as internal standards and to compensate for DDVP formed during the workup procedure. The results were related to erythrocyte and plasmacholinesterase determinations. The method described makes it possible to study pharmacokinetics in man and to relate this information to therapeutic effects. It is proposed that metrifonate acts as a slow release formulation for DDVP.

Adult↗

PubMed1979

Effect of physostigmine and atropine on acetylcholine turnover in mouse brain.

The effect of physostigmine salicylate (0.5 mg/kg, i.p.) alone and in combination with atropine sulfate (25 mg/kg, i.p.) on levels of acetylcholine (ACh) and choline (Ch) and turnover of ACh has been studied in whole brain and striatum of mice. The animals were killed by focussed microwave irradiation and the turnover of ACh was studied after i.v. injection of deuterium labelled Ch by employing mass fragmentography. Physostigmine increased the levels of ACh in whole brain from 24.5--28.0 nmol/g(P less than 0.001) whereas there was no significant increase in striatum. The levels of Ch were also increased. The turnover rate of ACh was decreased in whole brain from 15.4 to 8.4 and in striatum from 52.9 to 24.4 nmol/g . min. Physostigmine given before or after atropine did not completely block the ACh lowering effect of atropine. When atropine was given before physostigmine the turnover rate of ACh in whole brain was increased to 24.2 nmoles/g . min. The results seem to indicate that there is no clear cut relation between the turnover rate and level of ACh in vivo. The increase of the turnover rate induced by atropine is masked unless a cholinesterase inhibitor is given to protect the newly synthesized labelled ACh released by atropine.

Acetylcholine↗

PubMed1979

Jaborandi: an interdisciplinary appraisal.

In spite of many references to Pilocarpus Jaborandi Holmes in ethnological and botanical sources and suggestions of its employment for a variety of diseases, it has not been possible to pin down the use of its leaves to any particular purpose amongst South American Indians. While the medically important jaborandis are species of Pilocarpus, it is true that this vernacular name is commonly applied to other rutaceous and numerous piperaceous plants as well. The introduction of jaborandi leaves to western medicine goes back to 1873, when Symphronio Coutinho went to Europe, taking with him samples of the leaves. The copious sweating and salivation brought about by the leaves attracted the attention of French physicians. Soon jaborandi leaves were being employed in the treatment of many diseases. In 1875, Hardy and Gerrard independently discovered the alkaloid pilocarpine. Most therapeutic applications of jaborandi leaves and pilocarpine fell into disuse and were discontinued. What remained was the use of the latter in ophthalmology, where it had been introduced as a miotic by Weber in 1876. The mixture of pilocarpine and another natural product, physostigmine, remains to this day one of the mainstays in ophthalmology.

Alkaloids↗

PubMed1978

Metrifonate. Summary of toxicological and pharmacological information available.

The organophosphorus compound 0,0-dimethyl-(1-hydroxy-2,2,2-trichloroethyl)-phosphonate was introduced as an insecticide, trichlorfon, in 1952 (Lorenz et al., 1955) and as a drug, metrifonate, in the treatment of schistosomiasis in 1960 (Lebrun and Cerf, 1960). This organophosphorus compound is unique in that it has been claimed not to be a direct acting cholinesterase inhibitor but being transformed nonenzymatically into an active component dichlorvos, 2, 2-dichlorovinyl dimethyl phosphate (DDVP). The evidence for this transformation has mostly been indirect. Recently it has been proved chemically and quantitatively that this transformation occurs in the animal body (Nordgren et al., 1978). Metrifonate is the sole organophosphorus compound currently studied clinically in schistosomiasis. A substantial therapeutic effect is obtained only in Schistosoma haematobium infections. In this review on available data of metrifonate it is suggested that further more detailed studies of both S. haematobium and S. mansoni are necessary. This should include studies of the enzymic properties of the worms and the reaction of their esterases towards both metrifonate and DDVP as well as the pharmacokinetics of these compounds in man. In addition there are still unsolved discrepancies reported regarding organ toxicity of the compound which may, however, be due to different grades of parity of the test material.

Animals↗

PubMed1978

Transformation and action of metrifonate.

Chemical formation of dichlorvos (2, 2-dichlorovinyl dimethyl phosphate) was found to occur in mouse brain after i.p. injection of metrifonate (2, 2, 2-trichloro-1-hydroxyethyl dimethyl phosphonate). A mass fragmentographic technique was used. Different isotopic variants were used both as internal standards and to compensate for dichlorvos formed during the workup procedure. The dichlorvos formed in vivo was found to have its maximal concentration a few minutes after the maximum of the metrifonate itself. The effect of metrifonate and dichlorvos on acetylcholine levels, acetylcholinesterase activity and synthesis rate of acetylcholine in mouse brain was also studied. In all three cases the effect of metrifonate was found to be prolonged and delayed as compared to the effect of dichlorvos. It is concluded that metrifonate acts as a slow release formulation in the body giving rise to dichlorvos nonenzymatically. This circumstance at least partly explains its efficacy in the treatment of schistosomiasis.

Acetylcholine↗

PubMed1978

Effect of occupational exposure to organophosphorus insecticides on neuromuscular function.

Neurophysiological investigations and determinations of cholinesterase activity on plasma and erythrocytes were carried out on 11 Swedish spraymen exposed to bromophos, diazinon, dursbane, and malathion. Plasma cholinesterase activity was significantly reduced after work, while erythrocyte cholinesterase activity was unchanged. In none of the workers with a decreased plasma cholinesterase activity after work could any related acute neuromuscular disturbance be detected when the men were tested with repetitive nerve stimulation and with single fiber electromyography. Signs of subclinical neuropathy were present as a slight reduction in sensory conduction velocity and increased fiber density in some workers.

Action Potentials↗

PubMed1977