HLö 7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases.

HLö 7 dimethanesulfonate (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2,4-bis [(hydroxyimino)methyl]pyridinium dimethanesulfonate) is a broad-spectrum reactivator against highly toxic organophosphorus compounds. The compound was synthesized by a new route with the carcinogenic bis(chloromethyl)ether being substituted by the non-mutagenic bis(methylsulfonoxymethyl)ether. The very soluble dimethanesulfonate of obidoxime was also prepared by this way. HLö 7 dimethanesulfonate is the first water-soluble salt of HLö 7 that should be suitable for the wet/dry autoinjector technology, because aqueous solutions of HLö 7 are not very stable (calculated shelf-life 0.2 years when stored at 8 degrees C, 1 M solution, pH 2.5). The crystalline preparation contains 96% of the syn/syn-isomer, less than 2% of the syn/anti-isomer and some minor identified by-products. HLö 7 was very efficient in reactivating acetylcholinesterase (AChE) blocked by organophosphates as long as ageing did not prevent dephosphylation. HLö 7 was superior to HI 6 (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2- [(hydroxyimino)methyl]pyridinium dichloride) in reactivating soman and sarin-inhibited AChE from erythrocytes, and literature data indicate that HLö 7 exceeds HI 6 by far in reactivating tabun-inhibited AChE. In atropine-protected, soman-poisoned mice HLö 7 was three times more potent than HI 6 (protective ratio 5 versus 2.5), and in sarin-poisoned mice HLö 7 was 10 times more potent than HI 6 (protective ratio 8 for both oximes). In atropine-protected guinea-pigs HLö 7 was less effective than HI 6 (protective ratio: 2.3 versus 5.2 for soman; 5.2 versus 6.8 for sarin; 4.3 versus 3.8 for tabun). The mean survival time of anaesthetized guinea-pigs exposed to 5 LD50 soman (6.3 min) was increased by atropine (27 min) and atropine + HLö (57 min). HLö 7 alone did not prolong the survival. The most impressive effect of HLö 7 was on respiration: 3 min after i.v. injection of HLö 7 and atropine, the depressed respiration increased rapidly to 60% of control and remained at that level during the observation period (60 min). With atropine alone, respiration recovered only slowly. Behavioural and physiologic parameters were determined in atropine-protected mice exposed to a sublethal soman dose. The running performance was significantly improved by HLö 7. Even central symptoms, e.g. hypothermia and convulsions, were decreased markedly by HLö 7 (evaluation 60 min after poisoning). The pharmacokinetic data for HLö 7 in male beagle dogs are similar to those of HI 6.(ABSTRACT TRUNCATED AT 400 WORDS)

Negative inotropic effects of tetrodotoxin and seven class 1 antiarrhythmic drugs in relation to sodium channel blockade.

The negative inotropic effect and the effect on action potential configuration were investigated for TTX and 7 class 1 antiarrhythmic drugs (aprindine, AR-LH 31, CCI 22277, disopyramide, mexiletine, quinidine and sparteine) in the isolated guinea-pig papillary muscle contracting at 1 Hz. The ratio of the molar concentration producing 50% reduction of Vmax to that reducing force of contraction by 50% ranged from 0.23 (sparteine) to 2.2 (disopyramide) showing that some of the drugs were more potent Na channel blockers than negative inotropic agents, while the reverse was true for others. With the exceptions of sparteine and AR-LH 31, all the drugs produced a larger negative inotropic effect than TTX at concentrations equieffective in reducing Vmax. Thus, blockade of Na channels can account for only part of the negative inotropic effect of aprindine, CCI 22277, disopyramide, mexiletine and quinidine. Even sparteine and AR-LH 31 showed a negative inotropic property independent of Na channel blockade because, unlike TTX and like all other agents, they retained their negative inotropic activity after inactivation of Na channels by elevated extracellular K concentration (24 mmol/l). Relative negative inotropic effects of lorcainide, Org 6001 and propafenone were similar at 5.9 and 24 mmol/l (K)o. In contrast, the -log molar IC50(Fc) of flecainide, prajmalium bitartrate and tocainide was significantly decreased (by 0.35 to 0.81 log units) if Na channels were inactivated by K depolarization. Ouabain-sensitive Na,K-ATPase was not inhibited by sparteine, while mexiletine and AR-LH 31 produced partial inhibition (each at 1 mmol/l). We conclude that the negative inotropic effect of class 1 antiarrhythmic drugs represents the sum of their Na channel blocking and additional drug-dependent inotropic properties. Quinidine, aprindine and mexiletine appear to be combined Na channel and Ca channel inhibiting agents thus causing a larger negative inotropic effect than TTX. However, a superimposed positive inotropic mechanism may also be operative in some antiarrhythmic drugs (sparteine, AR-LH 31, high concentrations of mexiletine).