Sameridine

In dermal/transdermal drug administration stratum corneum (SC) is often the rate-limiting step. Furthermore, the intercellular lipid domain of SC is nowadays widely accepted as the major contributor to the skin barrier. The current work investigates whether the difference in the level of topical efficacy of local anesthetic compounds correlates with the type of interaction between the drug and the intercellular lipids of SC. Therefore, local anesthetics of varying topical efficacy were evaluated with respect to their effect on the morphology of various model lipid systems using small and wide angle X-ray diffraction (SWAXD) and differential scanning calorimetry (DSC). The model lipids used were glyceryl monooleate, sphingomyelin and lipids isolated from human SC. Furthermore, partitioning into isolated human SC as well as permeation through isolated human SC and human tape-stripped skin were investigated in vitro. The results indicate that local anesthetics may act as their own permeation enhancers by increasing the degree of hydrocarbon chain fluidity of the intercellular lipids. Eventually these interactions may induce non-lamellar reversed types of liquid crystalline structures locally in SC, which further facilitate the drug mobility. The large difference in topical efficacy of the investigated local anesthetics could not be explained simply by looking at their effect on the phase behavior of lipid model systems. Despite the similarities in physicochemical properties of these substances, the in vitro skin permeability differed markedly (AD>EMLA>lidocaine>prilocaine>sameridine). Thus, it was concluded that sufficient drug permeability over SC is essential to obtain local anesthesia by blocking the superficial nociceptors.

Research into local anaesthetic mechanisms over the past few years has focused on two main issues. First, attention has focused on development of compounds with fewer side effects, better sensory/motor separation and longer duration of action; this has resulted in the introduction of ropivacaine and levobupivacaine into clinical practice. These agents have a lesser cardiotoxic effect than older compounds, and ropivacaine may in addition offer better sensory/motor separation. Several other compounds, including tonicaine and sameridine, are under investigation. In addition, the local anaesthetic properties of amitryptiline are being studied, and liposome encapsulation of local anaesthetics appears able to confer new pharmacokinetic properties on common drugs. Second, the molecular basis for several local anaesthetic actions that are not mediated by sodium channels has become a topic of interest. The mechanisms that underlie anti-inflammatory and antithrombotic actions are at present being unravelled. How local anaesthetics potentiate antitumour agents, protect neuronal tissue and prevent bronchial reactivity is less clear, but the potential clinical benefits of these effects deserve further exploration.