“The pharmacokinetics of local anaesthetics can be significantly influenced by time of day of administration. This observation is rather new and has clinical implications. Moreover, chronokinetics can, but must not always, be responsible for daily variation in drug effects and/or side effects. Thus, temporal variations of local anaesthetics in experimental or clinical practice need to be taken into account because these drugs are very often used. Temporal periodicity analyses of therapeutic/toxic ratios may eventually contribute to a better understanding of the mortality and margin of safety of local anaesthetics.”

Re: therapeutic/toxic ratios

“Love and marriage, love and marriage, go together like a horse and carriage.”

Therapy and toxicity go together like lemon juice and paper cuts.

“[John] O’Neill and [Akhilesh] Reddy demonstrated that, in red blood cells from three individuals, peroxiredoxin levels stayed constant, but pairs of the proteins bound together and came apart in a 24-hour cycle. This cycle was temperature compensated—it retained its periodicity over three days at both 37ºC and 32ºC. (They tried putting the cells at 42ºC, but they died.) The peroxiredoxins maintained their cycles even in constant light. The cycle could also be entrained. When the cells were exposed to alternating high and low temperatures, they adjusted their schedules accordingly, even if that required them to completely reverse the phase of their cycle.

“All that happened without gene transcription. Hemoglobin molecules in these cells also bind together, and they also do so in a rhythmic manner, but it’s not yet known if hemoglobin’s oscillations are temperature compensated or entrained. The researchers thought that these rhythms might correlate with metabolic pathways and, when they checked, they found that ATP levels in red blood cells also oscillated in 24-hour cycles.”