Isobolographic Analysis of the Antinociceptive Interaction between Ursolic Acid and Diclofenac or Tramadol in Mice

Abstract

It is considered that natural products used in folk medicine can potentiate the effect of drugs. The aim of this study was to evaluate the pharmacological interaction between ursolic acid, a triterpene isolated from herbal medicines to treat pain, and the analgesics diclofenac or tramadol. Individual dose-response curves of the antinociceptive effect of these compounds were built to calculate the ED50, as well as the pharmacological interaction, by using isobolographic analysis. All treatments decreased significantly and in a dose-dependent manner the writhing behavior with ED50 values of 103.50 ± 19.66, 20.54 ± 6.05, and 9.60 ± 1.69 mg/kg, for ursolic acid, diclofenac, and tramadol, respectively. An isobolographic analysis allowed the characterization of the pharmacological interaction produced by a fixed ratio combination of 1 : 1 and 1 : 3 of equi-effective doses of these compounds. Theoretical antinociceptive ED50 values of ursolic acid-diclofenac were 62.12 ± 10.28 and 41.43 ± 6.69 mg/kg, respectively, not statistically different from those obtained experimentally (44.52 ± 5.25 and 44.89 ± 49.05 mg/kg, respectively), reporting an additive interaction. Theoretical antinociceptive ED50 values of ursolic acid-tramadol (56.56 ± 9.87 and 33.08 ± 5.07 mg/kg, respectively) were significantly lower than those observed experimentally (138.36 ± 49.05 and 67.34 ± 18.98 mg/kg, respectively) reporting antagonism in this interaction. Antinociceptive response obtained from isobolograms in the writhing test was corroborated by using formalin test in mice. Adverse effects such as gastric damage in the ursolic acid-diclofenac combination did not increase in an additive form similarly as with antinociception. Conversely, sedative response was significantly increased in the ursolic acid-tramadol combination. As observed in the formalin test, the antagonism on the antinociceptive response between ursolic acid and tramadol (1 : 1) was not reverted in the presence of the opioid antagonist naltrexone (1 mg/kg, i. p.). These results provide evidence for a differential pharmacological interaction, in which ursolic acid does not interfere with the antinociceptive effect of diclofenac but antagonizes that obtained with tramadol in an independent opioid mechanism. Therefore, medicinal plants containing abundant presence of ursolic acid may also modify efficacy in the alternative combinations for the pain therapy.

Chemical Fingerprint and Multicomponent Quantitative Analysis for the Quality Evaluation of Cyclocarya paliurus Leaves by HPLC–Q–TOF–MS

“…As shown in Table 6 , arjunolic acid, cyclocaric acid B, pterocaryoside B and pterocaryoside A were found to be abundant in all samples. In addition, cyclocaric acid B, pterocaryoside B and pterocaryoside A were unique constituents detected from C. paliurus leaves, which can be used as characteristic compounds to identify the authenticity of this plant [ 14 , 15 , 16 , 17 ]. Our results showed that the samples from Jiangxi Province (S14 and S15) contained the highest levels of the detected triterpenoid components, followed by the samples from Liping of Guizhou province (S6) and Jianghua of Hunan Province (S10).…”

“…Acetonitrile was of HPLC grade from Tedia (Fairfield, OH, USA); deionized water was further purified by a Milli-Q purification system (Millipore, Millford, MA, USA); HPLC-grade formic acid was purchased from Aladdin Co., Ltd. (Shanghai, China), and other reagents were all of analytical reagent grade. The reference standards of 3- O -caffeoylquinic acid, 4- O -caffeoylquinic acid, 4,5-di- O -caffeoylquinic acid, quercetin-3- O -glucuronide, quercetin-3- O -galactoside, isoquercitrin, kaempferol-3- O -glucuronide, kaempferol-3- O -glucoside, quercetin-3- O -rhamnoside, hederagenin and oleanolic acid were purchased from Shanghai Yuanye Biotechnology Co., Ltd. (Shanghai, China), and arjunolic acid was purchased from BioBioPha Co., Ltd. (Kunming, China), whereas kaempferol-3- O -rhamnoside, cyclocaric acid B, pterocaryoside A and pterocaryoside B were isolated and purified previously from the leaves of C. paliurus in the laboratory of China Pharmaceutical University (Nanjing, China) and were elucidated by comparison of spectral data (UV, MS, 1 H-NMR, 13 C-NMR) with those of published references [ 16 , 17 ]. The purity of each compound was determined to be more than 98% by normalization of the peak area detected by HPLC–UV.…”

“…The chemical investigations indicated that the leaves of C. paliurus contained abundant physiologically active compounds, such as flavonoids, phenolic acids, triterpenoids and polysaccharides [ 3 , 6 , 12 , 14 ]. It is noteworthy that several distinctive triterpene compounds named cyclocarioside I, cyclocarioside II, cyclocarioside III, pterocaryoside A, pterocaryoside B and cyclocaric acid B were only isolated and identified from the leaves of C. paliurus [ 14 , 15 , 16 , 17 ]. Since most botanical extracts have the therapeutic or preventable effects based on the synergic effects of their multiple components and multiple targets, it is insufficient to determine merely several markers of bioactive constituents in the complex botanical extracts [ 18 ].…”

Coadministration of Tramadol and Tizanidine in an Experimental Acute Pain Model in Rat

“…Thus, our study is the first report on the antagonistic activity of tramadol and tizanidine in acute inflammatory pain. However, previous studies have reported that tramadol has shown an antagonistic interaction effect with metamizol [Poveda et al., ], rofecoxib [García‐Hernández et al., ], dexketoprofen [Miranda et al., ], pregabalin [Keyhanfar et al., ], and ursolic acid [Déciga‐Campos et al., ]. The mechanism underlying these antagonistic interactions remains to be elucidated.…”

Ursolic acid loaded-mesoporous hydroxylapatite/ chitosan therapeutic scaffolds promote the bone regeneration

“…The UA drug was extracted from many plants such as the whole grass of the Labiatae plant, Prunella vulgaris, and the leaves of the holly, holly, iron holly leaves [33]. The UA is a triterpenoid compound found in natural plants and has many biological effects such as sedative [34], anti-in ammatory [35], antibacterial [36], and immune defense responses [37]. The Ursolic acid (UA), also promote osteoblast differentiation and new bone formation.…”