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Treatment of Poisoning by Soman. Leadbeater, L., INNS, R. H. AND RYLANDS, J. M. (1985). . 5, S225–S231. The efficacies of a number of drug treatment combinations in protecting guinea pigs against the lethal and incapacitating effects of soman (and sarin) have been determined. Incapacitation was studied using a swimming test which is a measure of gross motor performance. The drug combinations employed had no effect on the swimming performance of unpoisoned animals. Pyridostigmine pretreatment supported by postpoisoning therapy with atropine, pralidoxime mesylate (P2S), and diazepam protected guinea pigs against the lethal actions of soman and sarin, but the treatment was less effective in protecting against the agent-induced decrements in swimming performance. Replacing pyridostigmine (a quaternary carbamate) by physostigmine (which readily enters the CNS) and introducing aprophen (an anti-cholinergic drug with a range of pharmacological actions) improved the protection achieved against both lethality and incapacitation. When the postpoisoning therapy was omitted, pretreatment with physostigmine and aprophen (or some other anti-cholinergic drug) gave significant levels of protection against both soman- and sarin-induced lethality and incapacitation. It is concluded that a number of different pharmacological actions are required to antagonize nerve agent-induced incapacitation and that they, and their relative importance, remain to be identified. [ABSTRACT FROM PUBLISHER]

Interferon-alpha (IFN-alpha) subtypes were separated by HPLC from the IFN mixtures produced by virus-stimulated human lymphoblastoid cells and leukocytes. Together with preparations of lymphoblastoid IFN and recombinant IFN-beta, these were tested in three human tumor cell lines derived from liver, lung, and neuroblasts. Their relative antiviral activities differed markedly: subtype IFN-alpha 8 was the most potent and IFN-alpha 1 the least. The results were broadly similar in all three cells, with some minor differences. when the same preparations were tested for inhibition of thymidine incorporation, the relative activities were quite different: subtypes IFN-alpha 10, IFN-alpha 17, IFN-alpha 21, and IFN-alpha 5 were now the most active, and IFN-alpha 2 was the least active. IFN-alpha 1 and IFN-alpha 8 had comparable intermediate activity. Thus, the differences in activity were not caused by degradation of some subtypes during their separation. IFN-alpha 8 not only had the greatest antiviral activity but also, like IFN-beta, induced an antiviral state in U1 mutant cell lines, which lack the tyrosine kinase, Tyk2, required for signal transduction by other IFN-alpha subtypes.

A polycythaemia vera patient who initially responded to recombinant IFN-alpha 2 (rIFN-alpha 2) treatment developed neutralizing antibodies (NA) against it and lost response. Despite raising the dose, clinical resistance persisted and NA increased when two alternative rIFN-alpha 2 preparations were used. When treatment was switched to lymphoblastoid IFN-alpha (lyIFN-alpha N1), clinical response was restored and maintained. During re-treatment, NA specific for the earlier rIFN-alpha 2 preparations redeveloped and cross-reacted extensively with each other but not with 'whole' lyIFN-alpha N1 and only minimally with the lyIFN-alpha 2 subtype within it. These findings demonstrate the relevance of NA specificities in the re-treatment of antibody-compromised patients.

Three hepatitis C patients out of 15 who received recombinant interferon-alpha 2a (rIFN-alpha 2a) therapy developed high levels of neutralizing antibody coincident with clinical relapse. On analysis, antibodies in their sera were found to also produce some neutralization of lymphoblastoid IFN. Purified lymphoblastoid IFN was separated chromatographically into 10 fractions, each containing one or two IFN-alpha subtypes, and these were used individually to examine the subtype specificity of the neutralizing antibodies in the patients' sera. All three sera neutralized all the subtypes present in the 10 lymphoblastoid IFN fractions. These findings may explain why some patients who develop antibody-mediated resistance to treatment with rIFN-alpha 2 preparations are unable to respond again when treated instead with a human cell derived preparation containing many IFN-alpha subtypes.

Reversed-phase high-performance liquid chromatography (RP-HPLC) was used to separate the tryptic peptides of beta-casein. A gradient of 0-50% acetonitrile in 0.1% trifluoroacetic acid at a flow-rate of 0.8 ml/min resolved ten of the thirteen peptides. A modified gradient resolved the three peptides eluted at ca. 25% acetonitrile. RP-HPLC proved superior to high-voltage paper electrophoresis in analysis time, resolution and flexibility. The methods developed for the analysis of proteolysis of the milk protein, beta-casein, are now being applied to study the action of extracellular proteases from dairy bacteria on milk proteins.

The efficacy of a number of bispyridinium compounds, including both oxime and non-oxime derivatives, has been determined against poisoning by sarin, soman, tabun and VX in guinea-pigs receiving various supporting treatments. In conjunction with atropine therapy only, the oximes were effective against sarin and VX poisoning and of them only the 4-substituted oximes were beneficial against tabun poisoning. None of the compounds was effective against poisoning by soman. When the supporting drug treatment consisted of pyridostigmine pretreatment and therapy with atropine and diazepam (this treatment itself gave considerable protection against organophosphate poisoning) both the non-oxime and oxime derivatives increased the protection against all four agents although obidoxime and TMB-4 were not beneficial against soman poisoning. The results are discussed in relation to published studies in which these compounds have been found to be beneficial against soman poisoning in atropine-treated rats and mice. It is suggested that the guinea-pig is a better model for predicting the efficacy of treatments for organophosphate poisoning in primate species.