Supra‐Additive Interaction of Docosahexaenoic Acid and Naproxen and Gastric Safety on the Formalin Test in Rats

Abstract

Preclinical Research The aim of this work was to evaluate the effect of docosahexaenoic acid (DHA) on the pharmacokinetics and pharmacodynamics-nociception-of naproxen in rats, as well as to determine the gastric safety resulting from this combination versus naproxen alone. Female Wistar rats were orally administered DHA, naproxen or the DHA-naproxen mixture at fixed-ratio combination of 1:3. The antinociceptive effect was evaluated using the formalin test. The gastric injury was determined 3 h after naproxen administration. An isobolographic analysis was performed to characterize the antinociceptive interaction between DHA and naproxen. To determine the possibility of pharmacokinetic interactions, the oral bioavailability of naproxen was evaluated in presence and absence of oral DHA. The experimental effective dose ED values (Zexp) were decreased from theoretical additive dose values (Zadd; P < 0.05). The isobolographic analysis showed that the combination exhibited supra-additive interaction. The oral administration of DHA increased the pharmacokinetic parameter AUC of naproxen (P < 0.05). Furthermore, the gastric damage induced by naproxen was abolished when this drug was combined with DHA. These data suggest that oral administration of DHA-naproxen combination induces gastric safety and supra-additive antinociceptive effect in the formalin test so that this combination could be useful to management of inflammatory pain. Drug Dev Res 78 : 332-339, 2017. © 2017 Wiley Periodicals, Inc.

Synergistic interaction between docosahexaenoic acid and diclofenac on inflammation, nociception, and gastric security models in rats

“…Nociception and antinociception were assessed in the formalin test as previously described (Arroyo‐Lira et al, , ; Ortiz, ; Ortiz et al, ). Briefly, 50 μl of diluted formalin (1%) were injected s.c. into the plantar surface of the right hind paw, and the incidence of spontaneous flinching behavior was quantified for 1 min every 5 minutes for a period of 60 min after injection.…”

“…The investigator performing the experiments was unaware of the treatments received by the rats. Drug doses and administration time schedules used were selected based on previous reports (Arroyo‐Lira et al, , ; Landa‐Juárez, Ortiz, Castañeda‐Hernández, & Chávez‐Piña, ; Ortiz et al, , ) and on pilot experiments from our laboratory.…”

“…Differential paw volume (DPV) data were determined using the formula: DPV = paw volume during 6 hr − basal paw volume. The area under the curve of the systemic anti‐inflammatory or antinociceptive effects produced by each individual and combined drug regimen was calculated as previously described (Arroyo‐Lira et al, , ; Ortiz et al, ). The percent anti‐inflammation or antinociception for each phase was calculated according to equation: …”

“…Recently, diclofenac combined with the H 1 antihistaminic pyrilamine (Ortiz, ), a Matricaria chamomilla extract (Ortiz et al, ) or the natural unsaturated monocyclic sesquiterpene alcohol, α‐bisabolol (Ortiz et al, ) showed synergistic interactions in the anti‐inflammatory and antinociceptive effects with a reduced gastric liability. DHA combined with the NSAIDs indomethacin (Arroyo‐Lira et al, ) and naproxen (Arroyo‐Lira, Rodríguez‐Ramos, Ortiz, Castañeda‐Hernández, & Chávez‐Piña, ) showed synergistic interactions in antinociception with an absence of NASID‐induced gastric damage. In addition to prostaglandin synthesis inhibition, some NSAIDs have additional antinociceptive actions via activation of potassium channels and the nitric oxide pathway (Ortiz et al, ; Ortiz, Castañeda‐Hernández, & Granados‐Soto, ; Ortiz, Granados‐Soto, & Castañeda‐Hernández, ).…”

Pharmacodynamic interaction of 3α‐hydroxymasticadienonic acid and diligustilide against indomethacin‐induced gastric damage in rats

“…In addition, other studies show that the combination of some compounds (gallic acid and famotidine) with antioxidant properties exerts a synergistic effect in aspirin plus pyloric ligation induced ulcer (Asokkumar, Sen, Umamaheswari, Sivashanmugam, & Subhadradevi, ). In addition, several studies tested the combination of natural compounds such as α‐bisabolol (Ortiz, Cariño‐Cortés, Ponce‐Monter, Castañeda‐Hernández, & Chávez‐Piña, ), citral (Ortiz, González‐García, Ponce‐Monter, Castañeda‐Hernández, & Aguilar‐Robles, ), curcumin (De Paz‐Campos, Ortiz, Chávez Piña, Zazueta‐Beltrán, & Castañeda‐Hernández, ), and docosahexaenoic acid (Arroyo‐Lira et al, ; Arroyo‐Lira, Rodríguez‐Ramos, Ortiz, Castañeda‐Hernández, & Chávez‐Piña, ; Miranda‐Lara, Ortiz, Rodríguez‐Ramos, & Chávez‐Piña, ), with the most relevant NSAIDs in the clinic (indomethacin, diclofenac, and naproxen) in order to exhibit their anti‐inflammatory and antinociceptive activity, and moreover the resulting gastric safety of the combination in murine models. Therefore, our study attempts to show the importance of the combination of two natural compounds, from two medicinal plants frequently used in traditional medicine in order to decrease the NSAID‐gastropathy.…”