Photostability of antidotal oxime HI-6, impact on drug development.

HI-6 exhibits superior efficacy in the therapy of intoxication by different highly toxic organophosphorus nerve agents. Therefore HI-6 is a promising candidate for the development of new antidotes against nerve agents. For ethical and safety reasons antidotes containing HI-6 should get marketing authorization. Active pharmaceutical ingredients of medicinal products have to fulfil regulatory conditions in terms of purity and stability. Photostability is an essential parameter in this testing strategy. HI-6 was tested under conditions of ICH Q1B 'Photostability testing of new drug substances and products'. The data showed a marked degradation of HI-6 after exposure to daylight. The mechanism of degradation could be detected as photoisomerism. The light burden dependent rate of photoisomerism was followed quantitatively. Based on these quantitative results on the amount of light induced isomeric product a pharmacological qualification was made. A standardized in vitro test showed a decreased ability of light exposed HI-6 to reactivate sarin- and paraoxon-inhibited human acetylcholinesterase. These results have an impact on the further development of antidotes containing HI-6, as light protection will probably be necessary during handling, packaging, storage and application.

Purity of antidotal oxime HI-6 DMS as an active pharmaceutical ingredient for auto-injectors and infusions.

As reactivators of inhibited acetylcholinesterase, oximes are essential antidotes in poisoning by organophosphorus compounds. Due to its superior efficacy in cases of soman, cyclosarin, and sarin poisoning, the oxime HI-6 represents a promising option for an active pharmaceutical ingredient (API) in the further development of antidote therapy for nerve agent poisoning. Developmental lots of HI-6 DMS (dimethanesulfonate) provided by different manufacturers were examined with respect to their content and purity with a view to their future use as an API. There are distinct differences in the HI-6 content from three manufacturers. With respect to purity, gradual differences arise with the known synthetic by-products as well as with unknown accompanying compounds. It became apparent that in the case of a modified synthesis using protective groups, the proportion of some synthesis by-products decreases considerably. With one exception, they are thus below the reporting threshold for API in accordance with pertinent regulatory guidelines. In HI-6, an unknown impurity always occurs, whose percentage necessitates identification due to regulations. This unknown impurity, which has not been described so far, could be identified as an isomer. These findings supply data required for the description of pharmaceutical quality in accordance with module 3 of a Common Technical Document (CTD). They thus contribute to the marketing authorization of this substance as an API for auto-injectors and infusions.

Plasma level of atropine after accidental ingestion of Atropa belladonna.

BACKGROUND: Ingestion of toxic plant constituents still poses a challenge in clinical management. The amount of berries ingested is often unclear and in the case of Atropa belladonna may affect clinical outcome. Plasma levels of atropine may thus be useful in confirming the cause of intoxication. CASE REPORT: A 48-year-old man had ingested three handfuls of Atropa belladonna. Within 6 h he experienced phases of disorientation, aggressiveness, and tachycardia. He was initially treated with diazepam, an intravenous infusion of physostigmine and activated charcoal. After temporary improvement his clinical condition worsened and he was transferred to our toxicological intensive care unit. Here, ongoing sedation and continuous administration of physostigmine was necessary because of disorientation. In the early phase of hospitalization, a blood sample was taken and a muscarinic receptor total binding equivalent to binding of 130 microg/L atropine was determined by a radio receptor technique. Within 2 days the patient recovered completely and was discharged in a good general condition. CONCLUSION: Receptor binding may help confirm diagnosis and elucidate mechanisms in this type of exposure.