Inhibitor Report for: Mylaxen

The effects of spinal cord transection and acidosis on succinylcholine (SCC)-induced hyperkalemia were studied in Sprague-Dawley rats. The effectiveness of pretreatment with subparalyzing doses ("self-taming") of SCC or with the cholinesterase inhibitor hexafluorenium bromide in preventing hyperkalemia was also studied. The increase in plasma potassium after administration of SCC (1 mg/kg) was found to be significantly increased 10 days after spinal cord transection. This potassium increase could not be prevented by pretreatment with either hexafluorenium (0.3 mg/kg) or subparalyzing doses (0.15 mg/kg) of SCC. Respiratory acidosis caused an increase in plasma K+ in both normal and in spinal cord transected rats. Acidosis had a synergistic effect on succinylcholine-induced hyperkalemia. These findings support the clinical practice of not using succinylcholine in patients at risk of having a pathological sensitivity to SCC. Furthermore, SCC may be especially dangerous when administered to patients who are acidotic.

Forty patients, half of them with normal kidney function, the other half anephric were included in the study. All received diphenhydramine, meperidine and atropine for premedication and droperidol, fentanyl, N2O and O2 for anesthesia. For endotracheal intubation and further relaxation 0.3 mg/kg hexafluorenium, followed in 5 minutes by 0.2 mg/kg succinylcholine were given intravenously. Anesthesia was maintained by 0.5 micrograms/kg increments of fentanyl, muscle relaxation by increments of 0.15 mg/kg or less hexafluorenium and 0.2 mg/kg or less succinylcholine, depending on the surgical time requirements. The drop in serum potassium concentration was sustained and similar in both groups. In the anephric group the drop after induction of neurolept anesthesia was statistically significant. The concentration remained low in both groups over the entire observation period. Unchanged serum sodium excluded hemodilution and the fact that there was no significant change in PvCO2 and pH mitigates against alkalosis as the cause for the observed drop. The anesthesia and muscle relation, as described, appears to be a suitable and hazard free alternative to other techniques.

1. The interaction of hexafluorenium with acetylcholine, carbachol and suxamethonium with regard to the depolarization of the end-plate of rat diaphragm was studied. The depolarization was measured with the moving meniscus technique of Fatt. The competitive antagonist d-tubocurarine was included in the studies. 2. Hexafluorenium inhibited acetylcholinesterase in the end-plate. 3. The receptors in the end-plate were desensitized by carbachol and suxamethonium. Hexafluorenium enhanced the desensitization by suxamethonium. d-Tubocurarine had no direct influence on desensitization 4. The desensitization of the receptors in rat diaphragm is compatible with a cyclic model of desensitization. 5. The desensitizing interaction of hexafluorenium with the receptors may explain the non-competitive antagonism with depolarizing drugs with regard to the depolarization of the end-plate and the synergism with these drugs with regard to the paralysis of the indirectly stimulated muscle reported earlier. 6. The affinities of carbachol, suxamethonium and d-tubocurarine to the sensitive receptors are 4.9, 5.2 and 6.8, respectively.

The effects of spinal cord transection and acidosis on succinylcholine (SCC)-induced hyperkalemia were studied in Sprague-Dawley rats. The effectiveness of pretreatment with subparalyzing doses ("self-taming") of SCC or with the cholinesterase inhibitor hexafluorenium bromide in preventing hyperkalemia was also studied. The increase in plasma potassium after administration of SCC (1 mg/kg) was found to be significantly increased 10 days after spinal cord transection. This potassium increase could not be prevented by pretreatment with either hexafluorenium (0.3 mg/kg) or subparalyzing doses (0.15 mg/kg) of SCC. Respiratory acidosis caused an increase in plasma K+ in both normal and in spinal cord transected rats. Acidosis had a synergistic effect on succinylcholine-induced hyperkalemia. These findings support the clinical practice of not using succinylcholine in patients at risk of having a pathological sensitivity to SCC. Furthermore, SCC may be especially dangerous when administered to patients who are acidotic.

Forty patients, half of them with normal kidney function, the other half anephric were included in the study. All received diphenhydramine, meperidine and atropine for premedication and droperidol, fentanyl, N2O and O2 for anesthesia. For endotracheal intubation and further relaxation 0.3 mg/kg hexafluorenium, followed in 5 minutes by 0.2 mg/kg succinylcholine were given intravenously. Anesthesia was maintained by 0.5 micrograms/kg increments of fentanyl, muscle relaxation by increments of 0.15 mg/kg or less hexafluorenium and 0.2 mg/kg or less succinylcholine, depending on the surgical time requirements. The drop in serum potassium concentration was sustained and similar in both groups. In the anephric group the drop after induction of neurolept anesthesia was statistically significant. The concentration remained low in both groups over the entire observation period. Unchanged serum sodium excluded hemodilution and the fact that there was no significant change in PvCO2 and pH mitigates against alkalosis as the cause for the observed drop. The anesthesia and muscle relation, as described, appears to be a suitable and hazard free alternative to other techniques.

Sixty patients, none of whom was suffering from renal failure, received neurolept anaesthesia. They were divided into six groups of 10 patients each. Groups I and IV, II and V, and III and VI were given suxamethonium 0.2, 0.6 and 1.0 mg kg-1 respectively. Groups IV-VI were pretreated with hexafluorenium 0.3 mg kg-1. The serum potassium concentration decreased significantly after the induction of anaesthesia and also following the administration of hexafluorenium. Neither suxamethonium 0.2 mg nor 0.6 mg kg-1 with or without hexafluorenium restored the potassium concentration to the control value. Suxamethonium 1.0 mg kg-1 alone caused the serum potassium to increase to values greater than control; hexafluorenium attenuated this effect. The combination of hexafluorenium and suxamethonium may be of benefit in patients who are anephric or are in chronic renal failure.

1. The interaction of hexafluorenium with acetylcholine, carbachol and suxamethonium with regard to the depolarization of the end-plate of rat diaphragm was studied. The depolarization was measured with the moving meniscus technique of Fatt. The competitive antagonist d-tubocurarine was included in the studies. 2. Hexafluorenium inhibited acetylcholinesterase in the end-plate. 3. The receptors in the end-plate were desensitized by carbachol and suxamethonium. Hexafluorenium enhanced the desensitization by suxamethonium. d-Tubocurarine had no direct influence on desensitization 4. The desensitization of the receptors in rat diaphragm is compatible with a cyclic model of desensitization. 5. The desensitizing interaction of hexafluorenium with the receptors may explain the non-competitive antagonism with depolarizing drugs with regard to the depolarization of the end-plate and the synergism with these drugs with regard to the paralysis of the indirectly stimulated muscle reported earlier. 6. The affinities of carbachol, suxamethonium and d-tubocurarine to the sensitive receptors are 4.9, 5.2 and 6.8, respectively.

1. The influence of the 2 alkane-bis-onium compounds hexafluorenium (HF1) and hexamethonium (C6) on human plasma cholinesterase (ChE) was studied with respect to the type of inhibition. 2. HF1 and C6 are reversible inhibitors of ChE. The inhibitory potency of HF1 (pI50 = 6.96; Ki = 2.4 x 10(-9)) is about 40 000-fold higher than that of C6 (pI50 = 2.4; Ki = 6.7 x 10(-2)). 3. The kinetic analysis displayed a competitive (C6) and a non-competitive (hf1) mechanism of action. 4. The inhibition of ChE by C6 is induced by a binding of C6 to the anionic site of the active center thus impairing the primary formation of the enzyme-substrate complex. HF1, however, is most probably bound to anionic side receptors in the vicinity of the active center; by that a conformational change of the enzyme protein is induced impairing the acylation step of the esteratic site.

The effect of hexafluorenium 0.3 mg/kg on the neuromuscular block of suxamethonium 0.1 mg/kg in a child with homozygote atypical plasma cholinesterase activity and in one of his normal brothers has been compared. In the normal child, hexafluorenium produced a marked potentiation of suxamethonium block, while partially antagonizing the block in the atypical homozygote child. In both situations, the hexafluorenium-suxamethonium block appeared to be antidepolarizing in nature as indicated by tetanic fade and post-tetanic facilitation. It is concluded that, in man, hexafluorenium can modify the action of suxamethonium by two different mechanisms. In patients with normal plasma cholinesterase activity, the anti-esterase effect predominates and results in marked potentiation of suxamethonium block, while in atypical homozygotes a direct antidepolarizing action at the neuromuscular junction may result in a diminished response.