Atoxyl - Atoxilo

The Atoxilo is the trade name aminophenyl arsenic acid. Its name refers to its reduced toxicity compared to arsenic acid. Synthesized by Pierre Antoine Béchamp in 1869, [ 1 ] it was used in the treatment of trypanosomiasis and syphilis.

Atoxyl Formula
Identifiers [ 2 ]
CAS number 98-50-0
PubChem 6432805
ChemSpider 7111
DrugBank DB03006
ChEBI CHEBI:49477
ChEMBL CHEMBL351769
Properties [ 2 ]
Molecular Form C6H8AsNO3
Molecular Mass 217,054 g / mol
Density 1.957 g/cm³
Melting point 232 °C
LD50 rats via sc 75 mg/Kg
LD50 mice via sc 400 mg/Kg

Introduction

About 32,000 organic compounds containing arsenic were made in the early 1990s. They were used to treat pellagra, malaria, or sleeping sickness (trypanosomiasis). At the Liverpool School of Tropical Medicine he had produced atoxyl (a pentavalent arsenical compound), which was used to treat sleeping sickness. However, the high arsenic content produced ocular atrophy, which prompted further studies. Ehrlich, and his colleague Alfred Bertheim, were the first to determine the chemical structure of Atoxil, synthesizing later derivatives in search of greater effectiveness. In 1905 structure-activity correlation was established. [ 3 ]

At present, the use of Atoxil is restricted to the veterinary field, for raising chickens, turkeys and pigs to stimulate growth and improve feed conversion. It is used in the feed for laying and breeder hens, it helps to improve feed efficiency. Its use is restricted to certain countries such as Canada or Ecuador. Atoxil should not be administered 5 days before slaughter for human consumption and should not be administered to females 15 days before parturition. [ 4 ]

Toxicity

The toxic effect of Atoxil was originally described by Miayamoto in 1931, later in 1951 Ruedi and Nassuphis studied the toxicity of atoxyl in the hair cells of the ear. In order to study the toxicity of atoxyl, Anniko and Wersall conducted a study in guinea pigs to see if atoxyl caused damage to cells in the ear. Concluding that treatment with atoxyl causes damage to hair cells in the ear of guinea pigs. In this study, a distinction is made between hair cells of the outermost part of the inner ear and the innermost cells of the inner ear.

  • The outermost hair cells: poisoning in the outermost hair cells resulted in an increase in the size of the cells as a consequence of the appearance of vesicles in their cytoplasm. In the early stages of intoxication no changes in the nucleus were observed; However, in more advanced stages of intoxication, a disintegration of the nucleus was observed, and as a consequence, a breakdown of chromatin. .
  • Inner hair cells : the innermost cells presented a greater resistance to the toxic effect of atoxyl, in these there was the appearance of vesicles of different sizes, giving rise to the densification of the cytoplasm. In the innermost cells, as opposed to the outermost, damage to the mitochondria occurred, and as in the outermost cells, the nucleus ended up disintegrating in advanced stages of intoxication. This greater resistance on the part of the innermost cells is a consequence of a higher rate of metabolism of the outer cells.

The fact that Atoxyl affects the outer hair cells more than the inner ones may be explained due to a higher rate of metabolization of the outer cells than the inner ones.The probable cause of the Atoxyl-induced sensory degeneration is due to a change primary in the morphology of the vascular stria that can result in an altered ionic composition of the endolymph. The damaged areas represent the regions in which the local metabolism of endolymph is altered, although direct toxic damage to the organ of Corti cannot be ruled out, after the above explained.
The importance of proper endolymph metabolism was demonstrated by Kimura (1967) by experimental endolymphatic duct obstruction, resulting in damage to the apical regions of the cochlea.
TheAtoxil causes damage to sensory cells, stria vascularis and Reissner's membrane , causing morphological damage similar to Meniêre's disease, but it has been proven that any similarity in morphological appearance could be a coincidence and of different origin. [ 5 ]

Ehrlich studies related to Atoxyl

An effective treatment of trypanosomiasis requires the use of high doses of the compound for a prolonged period, which causes an increase in the risk of blindness due to optic nerve atrophy.

Ehrlich, in search of Atoxil derivatives, modified the substituents of the amino group in search of new compounds with greater efficiency and less toxic effects: less toxic compounds resulted, but when the high doses necessary for the treatment were administered, the experimental mice began to move uncontrollably in circles due to damage to the vestibular nerve. Furthermore, it was found that these new compounds were not effective in vitro and that they were activated (by reduction) within the body.
To test this hypothesis, they artificially obtained two products resulting from the reduction of Atoxil. One of them, arsenic oxides or arsenicides, were effective against Trypanosomes (in rats), but were highly toxic to the host. The second product, arsenobenzenes, although not as potent as the previous ones, proved to have less toxic effects and their administration in low doses avoided the problem of neurotoxicity. This group caught the attention of the Ehrlich task force. These good results in mice caused it to be tested in humans, with good results, except in a small group that demonstrated a severe hypersensitivity reaction.
Erlich also proposed another derivative of Atoxyl, adding a hydroxyl group in position 4 on the benzyl ring. This product, Arsenophenol, was clearly effective against Trypanosomes, however it had a high propensity for oxidation and was difficult to purify. The addition of a new substituent adjacent to the hydroxyl group, gave rise to a compound whose efficacy could not be verified, but which subsequently, in a new pharmacological evaluation, showed its effectiveness against syphilis. [ 3 ]

Bibliography

  1. Granados Jarque, Ricardo (1983). Essential compendium of pharmaceutical chemistry . Reverted. p. 480. ISBN 84-291-7321-8 .
  2. a b PubChem. "Arsanilic Acid" (in English) . Retrieved November 25, 2013 .
  3. a b Bosch, Félix; Laia Rosich (agosto de 2008). «The Contributions of Paul Ehrlich to Pharmacology: A Tribute on the Occasion of the Centenary of His Nobel Prize». Pharmacology (82): 171-179. doi:10.1159/000149583.
  4. ^ Canadian Food Inspection Agency. "Arsanilic acid" (in English) . Archived from the original on December 13, 2012 . Retrieved December 3, 2013 .
  5. Anniko, Matti (mayo de 1976). «Atoxyl-Induced Damage to the Sensory Cells in the Organ of Corti in the Guinea Pig Cochlea». Springer-Verlag (21): 267-277.