JMF2-1, a lidocaine derivative acting on airways spasm and lung allergic inflammation in rats.
BACKGROUND
Prior reports show that nebulized lidocaine might be an effective treatment for asthma.


OBJECTIVE
We sought to determine the anti-inflammatory and spasmolytic effects of lidocaine and its analogue, JMF2-1, which we have synthesized for reduced local anesthetic activity.


METHODS
Blockade of Na(+) currents was assayed in cultured GH(3) cells by using the patch-clamp technique, whereas anesthesia was assessed in a cutaneous pinching test in rats. Lidocaine and its analogue were nebulized into sensitized rats for evaluation of their effectiveness on airways spasm and inflammation induced by methacholine and allergen, respectively. Tissue histamine release and tracheal spasm triggered by allergen challenge in the absence and presence of these treatments were also examined in vitro.


RESULTS
The 50% inhibitory concentration values for blockade of Na(+) currents after treatment with JMF2-1 (25.4 mM) was remarkably higher than that of lidocaine (0.18 mM), which is consistent with the weak anesthetic capacity of this analogue. In contrast, JMF2-1 was more potent than lidocaine in inhibiting allergen-induced histamine release and tracheal spasm. In in vivo settings methacholine-induced increase in lung resistance (145%) significantly reduced to 72% and 47% after lidocaine and JMF2-1 treatment, respectively. Both treatments inhibited by about 81% allergen-evoked eosinophil accumulation into the lung tissue.


CONCLUSIONS
Replacement of the 2,6-dimethyl radicals by the 2-trifluormethyl group on the benzene ring of lidocaine significantly reduces anesthetic activity, preserving its ability to prevent key aspects of the allergic inflammatory response in the lung.


CONCLUSIONS
Nebulized JMF2-1 might be a means of achieving the antiasthmatic effects of lidocaine without the anesthetic effects.
da Costa
Jorge Carlos Santos
JC
Department of Physiology and Pharmacodynamics, IOC, Oswaldo Cruz Foundation (FIOCRUZ), Rio de Janeiro, Brazil.
Olsen
Priscilla Christina
PC
de Azeredo Siqueira
Rodrigo
R
de Frias Carvalho
Vinícius
V
Serra
Magda Fraguas
MF
Alves
Luiz Anastácio
LA
Faria
Robson Xavier
RX
Xisto
Debora Gonçalves
DG
Rocco
Patricia Rieken Macêdo
PR
Cordeiro
Renato Sérgio Balão
RS
Rodrigues E Silva
Patrícia Machado
PM
Martins
Marco Aurélio
MA
D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D006632:Histamine / Q000378:metabolism; D007958:Leukocyte Count; D008012:Lidocaine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D010047:Ovalbumin; D051381:Rats; D017208:Rats, Wistar; D012130:Respiratory Hypersensitivity / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D012640:Seizures / Q000139:chemically induced; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000502:physiology; D014132:Trachea / Q000187:drug effects / Q000503:physiopathology
D000777:Anesthetics; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D006632:Histamine; D010047:Ovalbumin; D008012:Lidocaine