4-Aminopyridine Reverses Saxitoxin (STX)- and Tetrodotoxin (TTX)-Induced Cardiorespiratory Depression in Chronically Instrumented Guinea Pigs

Abstract

. (1997). Fundam. Appl. Toxicol 38,[75][76][77][78][79][80][81][82][83][84][85][86][87][88] The extent to which cardiorespiratory infirmity and other sublethal effects of saxitoxin (STX) and tetrodotoxin (TTX) can be reversed by 4-aminopyridine (4-AP) was investigated in guinea pigs chronically instrumented for the concurrent electrophysiological recordings of electrocorticogram (ECoG), diaphragmatic electromyogram (DEMG), Lead II electrocardiogram, and neck skeletal muscle electromyogram. Animals were intoxicated with either STX or TTX (2 and 3 /xg/kg, im) to produce a state of progressive cardiorespiratory depression (depicted by decreasing DEMG amplitude, bradypnea, and bradycardia). At the point where cardiorespiratory performance was most seriously compromised («30 min posttoxin), 4-AP (1 or 2 mg/kg, im) was administered. The therapeutic effect of 4-AP was striking in that, within minutes, the toxin-induced diaphragmatic blockade, bradypnea, bradycardia, and depressed cortical activity were all restored to a level either comparable to, or surpassing, that of control. The optimal 4-AP dose level was determined to be 2 mg/kg (im) based on analyses of cardiorespiratory activity profiles throughout the course of intoxication and 4-AP treatment. At the dose levels (either 1 or 2 mg/ kg) used to restore ventilatory function and cardiovascular performance, 4-AP produced no sign of seizures and convulsions. Although less serious secondary effects such as cortical excitant/arousal effect (indicated by ECoG power spectral analysis) and transient periods of skeletal muscle fasciculation were observed, these events were of minor concern particularly in view of the remarkable therapeutic effects of 4-AP. © i»»7 society of Toxicology.Saxitoxin (STX) and tetrodotoxin (TTX) are among the deadliest nonprotein neurotoxins known (lethal dose in guinea pigs «*5 ^g/kg, im; unpublished observations).

Tetrodotoxin: Chemistry, Toxicity, Source, Distribution and Detection

“…Several treatments for TTX poisoning have been discussed earlier in the text ( Section 7.6 ). Interestingly, 4-aminopyridine was observed to reverse the effect of saxitoxin and tetrodotoxin in mice without any side effects such as seizure or convulsions [ 231 , 232 ]. The optimal 4-AP dose was determined as 2 mg/kg (im) [ 232 ].…”

Safety issues of compounds acting on adenosinergic signalling

“…Saxitoxin binds with high affinity on voltage‐gated sodium ion channels, thus preventing the influx of Na + (Figure ). Membrane depolarization in nerves and skeletal muscles is blocked, which causes a disease known as paralytic shellfish poisoning …”

“…Membrane depolarization in nerves and skeletal muscles is blocked, which causes a disease known as paralytic shellfish poisoning. [78,79]…”

“…[12][13][14][15][16] Here, mentioned massive investments were possible only after thorough due diligence of the field by Sitkovsky research team that advocated the use of synthetic A 2A AdR antagonists to improve immunotherapeutic treatment of numerous blood and solid organ cancers. Regarding the safety Figure 5 Saxitoxin blocks sodium voltage-gated channels as described by Chang et al [78] profile, many A 2A AdR antagonists were already in clinical trials for PD and were well tolerated, without severe immune-related toxicities, but it is important to carefully consider the known cardiovascular, neurological and proinflammatory effects of A 2A AdR and A 2B AdR antagonists, such as caffeine, together with differences comparing acute and chronic intake. [86,87] Due to demonstrated treatment options (PD and cancer immunotherapy), novel A 2A AdR antagonists with improved physicochemical, pharmacokinetic and pharmacological properties are being progressively developed.…”

BenzylN-(4-pyridyl)carbamate

“…The title compound, (I), a 4-aminopyridine analog, was synthesized for investigation of the nature of its reversion tetrodotoxin-induced cardiorespiratorydepression (Chang et al, 1997). The crystal packing is stabilized by stronger N-…”