INQUISUR   21779
INSTITUTO DE QUIMICA DEL SUR
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Analgesic properties of new copper(II) coordination complexes with Fenoprofen
Autor/es:
AGOTEGARAY, MARIELA A.; GUMILAR, FERNANDA A.; MINETTI, SILVIA A; QUINZANI, OSCAR VALENT¨ªN
Lugar:
C¨®rdoba
Reunión:
Congreso; Primera Reuni¨®n Internacional de Ciencias Farmace¨²ticas (RICIFa 2010); 2010
Institución organizadora:
Universidad Nacional de C¨®rdoba
Resumen:
Introduction
The analgesic effect of copper(II) coordination complexes with non-steroidal antiinflammatory
drugs (NSAIDs) is an issue of debate. Some authors sustain that the analgesic
action becomes enhanced when the NSAID forms a coordination compound with copper(II) (1),
meanwhile others have found that the complexation does not produce changes on the analgesic
effect of the parent drug (2).
In this work, we investigate the analgesic effect of two new copper(II) coordination
complexes with the non steroidal anti-inflammatory drug Fenoprofen, Cu2(Fen)4(dmf)2 (Fen:
fenoprofenate anion; dmf: dimethylformamide) and Cu2(Fen)4(caf)2 (caf: cafeine) using acetic
acid-induced writhes and formalin test. These two different analgesic testing models were
employed with the aim of identifying peripheral and central effects of the test substances. Acetic
acid produces a painful reaction and acute inflammation in the peritoneal area and induces
abdominal writhing which is a visceral pain model (3,4). The formalin test is considered a
model for pain (5) and it is an effective way to measure the peripheral and central pain.2(Fen)4(dmf)2 (Fen:
fenoprofenate anion; dmf: dimethylformamide) and Cu2(Fen)4(caf)2 (caf: cafeine) using acetic
acid-induced writhes and formalin test. These two different analgesic testing models were
employed with the aim of identifying peripheral and central effects of the test substances. Acetic
acid produces a painful reaction and acute inflammation in the peritoneal area and induces
abdominal writhing which is a visceral pain model (3,4). The formalin test is considered a
model for pain (5) and it is an effective way to measure the peripheral and central pain.2(Fen)4(caf)2 (caf: cafeine) using acetic
acid-induced writhes and formalin test. These two different analgesic testing models were
employed with the aim of identifying peripheral and central effects of the test substances. Acetic
acid produces a painful reaction and acute inflammation in the peritoneal area and induces
abdominal writhing which is a visceral pain model (3,4). The formalin test is considered a
model for pain (5) and it is an effective way to measure the peripheral and central pain.
Materials and methods
The synthesis of Cu2(Fen)4(dmf)2 has been previously described (6). From this one
dissolved in acetone, Cu2(Fen)4(caf)2 was prepared by the addition of an ethanolic solution of
caffeine. After the reaction, crystals were obtained by the diffusion of acetonitrile.
For the writhing test, four groups of mice were orally treated with Cu2(Fen)4(dmf)2 (26
mg/kg ), Cu2(Fen)4(caf)2 (31 mg/kg), Fenoprofen calcium salt as uncomplexed parent drug
(21mg/kg), and the control one which received only vehicle (1% CMC, 0.1% Tween80). Then,
60 minutes later nociception was induced by an intraperitoneal injection of 0.5% acetic acid
solution (10mL/kg). After injection, each animal was isolated in an individual box to be
observed during 20 minutes. The number of writhing and stretching was recorded.2(Fen)4(dmf)2 has been previously described (6). From this one
dissolved in acetone, Cu2(Fen)4(caf)2 was prepared by the addition of an ethanolic solution of
caffeine. After the reaction, crystals were obtained by the diffusion of acetonitrile.
For the writhing test, four groups of mice were orally treated with Cu2(Fen)4(dmf)2 (26
mg/kg ), Cu2(Fen)4(caf)2 (31 mg/kg), Fenoprofen calcium salt as uncomplexed parent drug
(21mg/kg), and the control one which received only vehicle (1% CMC, 0.1% Tween80). Then,
60 minutes later nociception was induced by an intraperitoneal injection of 0.5% acetic acid
solution (10mL/kg). After injection, each animal was isolated in an individual box to be
observed during 20 minutes. The number of writhing and stretching was recorded.2(Fen)4(caf)2 was prepared by the addition of an ethanolic solution of
caffeine. After the reaction, crystals were obtained by the diffusion of acetonitrile.
For the writhing test, four groups of mice were orally treated with Cu2(Fen)4(dmf)2 (26
mg/kg ), Cu2(Fen)4(caf)2 (31 mg/kg), Fenoprofen calcium salt as uncomplexed parent drug
(21mg/kg), and the control one which received only vehicle (1% CMC, 0.1% Tween80). Then,
60 minutes later nociception was induced by an intraperitoneal injection of 0.5% acetic acid
solution (10mL/kg). After injection, each animal was isolated in an individual box to be
observed during 20 minutes. The number of writhing and stretching was recorded.2(Fen)4(dmf)2 (26
mg/kg ), Cu2(Fen)4(caf)2 (31 mg/kg), Fenoprofen calcium salt as uncomplexed parent drug
(21mg/kg), and the control one which received only vehicle (1% CMC, 0.1% Tween80). Then,
60 minutes later nociception was induced by an intraperitoneal injection of 0.5% acetic acid
solution (10mL/kg). After injection, each animal was isolated in an individual box to be
observed during 20 minutes. The number of writhing and stretching was recorded.2(Fen)4(caf)2 (31 mg/kg), Fenoprofen calcium salt as uncomplexed parent drug
(21mg/kg), and the control one which received only vehicle (1% CMC, 0.1% Tween80). Then,
60 minutes later nociception was induced by an intraperitoneal injection of 0.5% acetic acid
solution (10mL/kg). After injection, each animal was isolated in an individual box to be
observed during 20 minutes. The number of writhing and stretching was recorded.
For the formalin test, 20 ¦Ìl of 2,5 % formalin was injected into the dorsal surface of the
left paw of mice, one hour after oral administration of complexes, Fenoprofen calcium salt or
vehicle. The time that animals spent on licking the injected paw was recorded. Two distinct
periods of intensive licking activity were identified and scored separately. The inicial
nociceptive scores normally peaked 5 minutes after formalin injection (early phase) and 15-30
minutes after injection (late phase), representing both the neurogenic and inflammatory pain
responses, respectively.
Results
Acetic acid-induced writhing
Treatment with Cu2(Fen)4(dmf)2, Cu2(Fen)4(caf)2 and Fenoprofen salt groups significantly
decreased the acetic acid-induced writhing response compared with the control: 89,7 %
(p<0.001), 89,8 % (p<0.001) and 45,2 % (p<0.05), respectively. When Fenoprofen calcium salt
was compared to the complexes, both Cu2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 decreased more
effectively the visceral pain (p< 0.001).2(Fen)4(dmf)2, Cu2(Fen)4(caf)2 and Fenoprofen salt groups significantly
decreased the acetic acid-induced writhing response compared with the control: 89,7 %
(p<0.001), 89,8 % (p<0.001) and 45,2 % (p<0.05), respectively. When Fenoprofen calcium salt
was compared to the complexes, both Cu2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 decreased more
effectively the visceral pain (p< 0.001).p<0.001), 89,8 % (p<0.001) and 45,2 % (p<0.05), respectively. When Fenoprofen calcium salt
was compared to the complexes, both Cu2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 decreased more
effectively the visceral pain (p< 0.001).2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 decreased more
effectively the visceral pain (p< 0.001).p< 0.001).
Formalin test
The time spent on licking the injured paw was significantly attenuated in the early phase by
complexes and Fenoprofen salt, but Cu2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 showed marked
inhibition (p < 0.001) of licking responses in the late phase when compared to the control and to
the uncomplexed parent drug.2(Fen)4(dmf)2 and Cu2(Fen)4(caf)2 showed marked
inhibition (p < 0.001) of licking responses in the late phase when compared to the control and to
the uncomplexed parent drug.p < 0.001) of licking responses in the late phase when compared to the control and to
the uncomplexed parent drug.
Conclusion
The results found in this work indicate that, although Cu2(Fen)4(dmf)2 and
Cu2(Fen)4(caf)2 produce similar effect than Fenoprofen calcium salt in central pain, both
complexes present a more potent analgesic effect for peripheral pain.2(Fen)4(dmf)2 and
Cu2(Fen)4(caf)2 produce similar effect than Fenoprofen calcium salt in central pain, both
complexes present a more potent analgesic effect for peripheral pain.2(Fen)4(caf)2 produce similar effect than Fenoprofen calcium salt in central pain, both
complexes present a more potent analgesic effect for peripheral pain.
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