Agastache mexicana is a plant in high demand that has long been used in Mexican folk medicine to treat anxiety, insomnia, and stomachache, among other afflictions. Ursolic acid and acacetin were isolated and identified as two possible active compounds of A. mexicana aerial parts. An antinociceptive response was demonstrated in a significant and dose-dependent manner with ursolic acid and acacetin (i. p. and p. o.) in comparison to the analgesic diclofenac by using the writhing test in mice. Moreover, acacetin also produced a significant concentration-dependent spasmolytic response with major efficacy compared to ursolic acid and papaverine by using rings from the isolated guinea pig ileum. These results provide evidence of the presence of two active constituents of Agastache mexicana reinforcing its utility as a therapy for visceral pain as used in traditional medicine.

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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.

Different studies in experimental diabetes models suggest that zinc oxide nanoparticles (ZnONPs) are useful as antidiabetic agents. However, this evidence was performed and measured in long-term treatments and with repeated doses of ZnONPs. This work aimed to evaluate the ZnONPs acute effects on glycemia during the next six h after an oral or intraperitoneal administration of the treatment in healthy and diabetic rats. In this study, the streptozotocin-nicotinamide intraperitoneal administration in male Wistar rats were used as a diabetes model. 10 mg/kg ZnONPs did not modify the baseline glucose in any group. Nevertheless, the ZnONPs short-term administration (100 mg/kg) induced a hyperglycemic response in a dose and route-dependent administration in healthy (130 ± 2 and 165 ± 10 mg/dL with oral and intraperitoneal, respectively) and diabetic rats (155 ± 2 and 240 ± 20 mg/dL with oral, and intraperitoneal, respectively). The diabetic rats were 1.5 fold more sensitive to ZnONPs effect by the intraperitoneal route. In conclusion, this study provides new information about the acute response of ZnONPs on fasting glycemia in diabetic and healthy rat models; these data are essential for possible future clinical approaches.

ZnO nanoparticles (ZnONPs) have been shown to have therapeutic potential in some diseases such as diabetes and cancer. However, concentration-dependent adverse effects have also been reported. Studies which evaluate the effects of ZnONPs on the cardiovascular system are scarce. This study aimed to evaluate the cardiovascular effects of a low dose of ZnONPs administered chronically in healthy rats. Changes in dyslipidemia biomarkers, blood pressure, aortic wall structure, vascular contractility, and expression of cannabinoid receptors in the aorta wall were evaluated. Healthy rats were divided into two groups: control or treated (one, two, and three months). The treated rats received an oral dose of 10 mg/kg/day. The results showed that treatment with ZnONPs induced dyslipidemia from the first month, increasing atherosclerosis risk, which was confirmed by presence of atherosclerotic alterations revealed by aorta histological analysis. In in vitro assays, ZnONPs modified the aorta contractile activity in response to the activation of cannabinoid receptors (CB1 and CB2). The expression of CB1 and CB2 was modified as well. Moreover, ZnONPs elicited an increase in blood pressure. In conclusion, long-time oral administration of ZnONPs induce dyslipidemia and atherosclerosis eliciting alterations in aorta contractility, CB1 and CB2 receptors expression, and an increase in blood pressure in healthy rats.