Chemical Constituents from Agave applanata and Its Antihyperglycemic, Anti-inflammatory, and Antimicrobial Activities Associated with Its Tissue Repair Capability.

Agave applanata is a Mexican agave whose fresh leaves are employed to prepare an ethanol tonic used to relieve diabetes. It is also applied to skin to relieve varicose and diabetic foot ulcers, including wounds, inflammation, and infections. In this study, the chemical composition of this ethanol tonic is established and its association with antihyperglycemic, anti-inflammatory, antimicrobial, and wound healing activities is discussed. The fresh leaves of A. applanata were extracted with ethanol : H2O (85 : 15). A fraction of this extract was lyophilized, and the remainder was partitioned into CH2Cl2, n-BuOH, and water. CH2Cl2 and n-BuOH fractions were subjected to a successive open column chromatography process. The structure of the isolated compounds was established using nuclear magnetic resonance and mass spectrometry spectra. The antihyperglycemic activity was evaluated through in vivo sucrose and glucose tolerance experiments, as well as ex vivo intestinal absorption and hepatic production of glucose. Wound healing and edema inhibition were assayed in mice. The minimum inhibitory concentrations (MICs) of the hydroalcoholic extract, its fractions, and pure compounds were determined through agar microdilution against the most isolated pathogens from diabetic foot ulcers. Fatty acids, ß-sitosterol, stigmasterol, hecogenin (1: ), N-oleyl-D-glucosamine, ß-daucosterol, sucrose, myo-inositol, and hecogenin-3-O-α-L-rhamnopyranosyl-(1 → 3)-ß-D-xylopyranosyl-(1 → 2)-[ß-D-xylopyranosyl-(1 → 3)-ß-D-glucopyranosyl-(1 → 3)]-ß-D-glucopyranosyl-(1 → 4)-ß-D-galactopyranoside (2: ) were characterized. This research provides evidence for the pharmacological importance of A. applanata in maintaining normoglycemia, showing anti-inflammatory activity and antimicrobial effects against the microorganisms frequently found in diabetic foot ulcers. This plant plays an important role in wound healing and accelerated tissue reparation.

Synergistic Herb-Herb Interaction of the Antinociceptive and Anti-Inflammatory Effects of Syzygium aromaticum and Rosmarinus officinalis Combination.

The use of alternative medicine to treat pain has been increased, and the combination of several medicinal plants for its relief is a common practice in traditional medicine. The present study is aimed at determining whether a combination of Syzygium aromaticum (S. aromaticum) and Rosmarinus officinalis L. (R. officinalis) potentiates their antinociceptive and anti-inflammatory effects. These effects were explored using the formalin and carrageenan assays in rats, respectively. Animals received local pretreatment with S. aromaticum oil or R. officinalis ethanolic extract (0.1-100 µg/paw) alone or combined in a 1 : 1 rate. Concentration-response curves were built to compare pharmacological responses after an individual administration of S. aromaticum, R. officinalis, or their combination. The pharmacological interaction was investigated by an isobolographic study using the EC50 of each component in a fixed 1 : 1 ratio. S. aromaticum and R. officinalis administered alone showed significant and concentration-dependent antinociceptive and anti-inflammatory effects, but R. officinalis was more potent than S. aromaticum in both the antinociceptive and anti-inflammatory effects (EC50 = 7.96 ± 0.6 µg/paw vs. EC50 = 41.6 ± 1.7 µg/paw; EC50 = 1.97 ± 0.3 µg/paw vs. EC50 = 26.9 ± 2.5 µg/paw, respectively). The isobolographic analysis of the combination of these species in a 1 : 1 ratio showed a synergistic interaction between S. aromaticum and R. officinalis since Z mix (experimental value) was lower than Z add (theoretical value) for both the antinociceptive effect (Z mix = 0.45 ± 0.1 < Z add = 24.8 ± 1.3) and the anti-inflammatory effect (Z mix = 5.2 ± 0.6 < Z add = 14.4 ± 2.2), suggesting a potentiation for both pharmacological effects. These results prove evidence of the efficacy of mixture herb-herb used in folk medicine for pain therapy. It also emphasizes the requirement of pharmacological studies to explore the efficacy and safety of herb interactions.

Quercetin decreases the antinociceptive effect of diclofenac in an arthritic gout-pain model in rats.

OBJECTIVE: To analyse the antinociceptive interaction between quercetin (QUER) and diclofenac (DIC) in experimental arthritic gout-pain. METHODS: The antinociceptive effect of DIC and QUER alone and in combination were evaluated using an arthritic gout-pain model. Pain was induced through intra-articular administration of uric acid in the rats and the treatments were administered 2 h later. Additionally, the cyclooxygenase (COX) activity was determined in rats treated with DIC, QUER and their combination. KEY FINDINGS: DIC induced a maximal effect of 69.7 ± 2.7% with 3.1 mg/kg; whereas QUER only produced 17.6 ± 2.6% with the maximal dose (316 mg/kg). Ten of twelve DIC + QUER combinations showed a lesser antinociceptive effect than DIC alone did (P < 0.05). Moreover, DIC reduced total-COX (70.4 ± 1.3 versus 52.4 ± 1.8 and 77.4 ± 9.0 versus 56.1 ± 1.3, P < 0.05) and COX-2 (60.1 ± 1.0 versus 42.4 ± 1.8 and 58.1 ± 2.4 versus 48.7 ± 1.3, P < 0.05) activity after 1 and 3 h, respectively. Nevertheless, only the COX-2 activity induced by DIC was prevented in the presence of QUER (63.2 ± 3.0 versus 60.1 ± 1.0 and 56.6 ± 1.3 versus 58.1 ± 2.4 at 1 and 3 h, respectively). CONCLUSIONS: All these data demonstrated that the simultaneous administration of QUER + DIC produces an unfavorable interaction on the antinociceptive effect of DIC. Therefore, this combination might not be recommendable to relieve arthritic gout-pain.

Pharmacological Analysis of the Anti-inflammatory and Antiallodynic Effects of Zinagrandinolide E from Zinnia grandiflora in Mice.

Zinagrandinolide E (1, ZGE) is an elemanolide with antinociceptive action isolated from Zinnia grandiflora (Asteraceae), valued in North México and southwestern United States for pain relief. Herein, we report the anti-inflammatory and antiallodynic action of ZGE (1) in carrageenan-induced inflammation and tactile allodynia in mice and in a neuropathic pain model in hyperglycemic mice. Local peripheral administration of ZGE (1-30 µg/paw) induced dose-dependent acute anti-inflammatory and antiallodynic effects. The anti-inflammatory effect was comparable to diclofenac (30 µg/paw). Intrathecal (i.t.) administration of ZGE (30 µg) in acute experiments did not affect carrageenan-induced inflammation but significantly reduced tactile allodynia in a dose-dependent fashion. In long-term experiments (15 or 6 days), using two different scheme treatments (pretreatment or post-treatment), ZGE (3-30 µg/paw) showed antiallodynic but not anti-inflammatory action. Local peripheral (3-30 µg/paw) or intrathecal (3-30 µg) administration of ZGE partially reversed tactile allodynia in hyperglycemic mice, better or comparable, respectively, with those of pregabalin (30 µg/paw or 30 µg i.t.). The effects were dose-dependent. According to the pharmacological tools employed, the anti-inflammatory and antiallodynic activities of ZGE are multitarget; these involve the opioidergic, serotoninergic, and GABAergic systems, as well as the NO-cGMP-ATP-sensitive K+ channel signaling pathway.

Study of Antispasmodic and Antidiarrheal Activities of Tagetes lucida (Mexican Tarragon) in Experimental Models and Its Mechanism of Action.

Tagetes lucida has been used in traditional medicine as a remedy to alleviate several gastrointestinal disorders that provoke stomachaches, abdominal cramps, and diarrhea. However, there is not enough scientific evidence that supports these effects. Therefore, the purpose of this study was to evaluate antispasmodic and antidiarrheal activities of aqueous extract of T. lucida (AqExt-TL) as well as its mechanism of action in experimental models. Antispasmodic activity and the mechanism of action of AqExt-TL were assessed on segments of the guinea pig ileum precontracted with KCl, acetylcholine (ACh), or electrical field stimulation (EFS). Furthermore, the antispasmodic effect of two coumarins (umbelliferone and herniarin) previously identified in this species was evaluated. Antidiarrheal activity of AqExt-TL was determined using the charcoal meal test in mice. AqExt-TL showed antispasmodic activity in segments of the guinea pig ileum precontracted with KCl (83.7 ± 1.9%) and ACh (77.2 ± 5.3%) at the maximal concentration; however, practically, it did not alter the contractions induced by EFS (10.1 ± 2.2%). Antispasmodic activity of AqExt-TL was not significantly altered by hexamethonium (a ganglionic blocker) or L-NAME (an inhibitor of nitric oxide synthase). However, this extract decreased the maximal contractile response to calcium (82.7 ± 8.5%), serotonin (68.1 ± 8.5%), and histamine (63.9 ± 5.9%) in their concentration-response curves. Umbelliferone and herniarin also induced an antispasmodic effect on tissues precontracted with KCl. In addition, low doses of AqExt-TL reduced to 50% the distance traveled by charcoal meal in the gastrointestinal transit model in mice as loperamide, an antidiarrheal agent, did. These results provided evidence of the antispasmodic and antidiarrheal activity of T. lucida, which supports its use in the folk medicine in relieving symptoms in some gastrointestinal disorders. In the antispasmodic effect, the blockade of histaminergic and serotoninergic pathway as well as the calcium channels seems to be involved. Finally, umbelliferone and herniarin could be partially responsible for the antispasmodic activity induced by T. lucida.

Antinociceptive effects of Salvia divinorum and bioactive salvinorins in experimental pain models in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Salvia divinorum Epling & Játiva is a Mexican plant used not only in rituals but also in traditional medicine for pain relief. One of the most known bioactive compounds is salvinorin A, which acts centrally in kappa-type opioid receptors. AIM OF THE STUDY: Despite its traditional use as a medicinal plant, there is not enough scientific investigation to reinforce its potential as analgesic. In this study, Salvia divinorum antinociceptive activity was evaluated in experimental models of nociceptive pain; the writhing test and formalin-induced licking behavior in mice. MATERIAL AND METHODS: Different Salvia divinorum extracts were prepared by maceration at room temperature in increased polarity (hexane, ethyl acetate and methanol). The ethyl acetate extract (EAEx) was chosen in order to be fractioned and to obtain a mixture of salvinorins. The antinociceptive effect of EAEx (3, 10, 30, and 100 mg/kg, i.p.) was compared with that of tramadol (a partial opioid agonist analgesic drug, 30 mg/kg, i.p.) and the mixture of salvinorins (30 mg/kg, i.p.). In addition, a participation of opioids (naloxone, NX 1 and/or 3 mg/kg, i.p.) and serotonin 5-HT1A receptors (WAY100635, 0.32 mg/kg, i.p.) was investigated as possible inhibitory neurotransmission involved. RESULTS: As a result, the EAEx produced significant and dose-dependent antinociceptive effect concerning salvinorins constituents. This effect was blocked in the presence of NX and WAY100635 in the abdominal test, but only by NX in the formalin-induced licking behavior. Whereas, the effect of salvinorins mixture involved opioids and serotonin 5-HT1A receptors. CONCLUSION: Data provide evidence of the potential of this species, where salvinorin A is in part responsible bioactive constituent involving participation of the opioids and/or 5-HT1A serotonin receptors depending on the kind of pain model explored.

Antinociceptive Potential of Zinnia grandiflora.

An aqueous extract prepared from the aerial parts of Zinnia grandiflora was found not to induce acute toxicity (LD50> 5g/kg, p.o.) in mice when tested by the Lorke method. This extract showed notable antinociceptive and anti-inflammatory actions when evaluated by the formalin- (ED50 = 224.62 ± 38.17 mg/kg, p.o.) and the carrageenan-induced paw edema models in mice, respectively. The organic-soluble fractions obtained by partitioning the infusion with CH2Cl2 and EtOAc were also active in the formalin test. The most important antinociceptive effect was observed with the CH2Cl2 fraction; extensive fractionation of the latter yielded three new elemanolides, namely, zinagranolides D-F (1-3), which were characterized structurally by spectroscopic means. The structure of compound 2 was established unequivocally by an X-ray crystallographic analysis. This compound exerted a significant antinociceptive effect in the formalin assay, better than that of diclofenac used as a positive control.

Spasmolytic effect of aqueous extract of Tagetes erecta L. flowers is mediated through calcium channel blockade on the guinea-pig ileum.

This study provides pharmacological evidence on the spasmolytic activity of Tagetes erecta L. (marigold or cempasúchil) on the guinea-pig ileum and presents data on its mechanism of action. The relaxant effect on KCl contractions was more marked with aqueous (AqEx) than with ethanol extracts (EtEx) of T. erecta flowers (55.6 ±â€¯11.0 vs 21.1 ±â€¯4.4%, respectively). In addition, the aqueous extract antagonized contractions elicited by EFS, but not by acetylcholine (73.5 ±â€¯1.9 vs 14.5 ±â€¯5.3%, respectively). These effects were not diminished by hexamethonium or L-NAME, but this extract caused a rightward shift in the Ca2+ concentration-response curves like that of verapamil. Quercetin and rutin, two flavonoids present in this plant, also showed spasmolytic effects (95.7 ±â€¯2.8 and 27.9 ±â€¯7.1%, respectively). Interestingly, in tissues without spasmogens, the extract induced contractions superimposed on their spontaneous activity. These results support the traditional use of T. erecta as a spasmolytic in folk medicine and suggest mainly that quercetin could be partly responsible for this effect. The spasmolytic effect appears to involve voltage-gated calcium channels, but not the nitric oxide pathway or the release of neurotransmitters from enteric neurons. Nevertheless, this plant could produce colic or stomachache as adverse effects in clinical situations in which these symptoms are not originally present.

Synthesis and antinociceptive evaluation of bioisosteres and hybrids of naproxen, ibuprofen and paracetamol.

The aim of this work was to design, synthesize and characterize the potential anti-nociceptive and anti-inflammatory activities of a new series of bioisosteres and hybrids from known non-steroidal anti-inflammatory drugs (NSAIDs). The compounds 4-(acetylamino)phenyl (2S)-2-(6-methoxy-2-naphthyl)propanoate (GUF-1) and 4-(acetylamino)phenyl 2-(R,S)-(4-isobutylphenyl)propanoate (GUF-2) were synthesized as hybrids (also known as heterodimers); whereas those named 2-(R,S)-(4-isobutylphenyl)-N-1H-tetrazol-5-ylpropanamide (GUF-3), (2S)-2-(6-methoxy-2-naphthyl)-N-1H-tetrazol-5-ylpropanamide (GUF-4), [2-(R,S)-N-hydroxy-2-[4-(2-methylpropyl)phenyl]propanamide] (GUF-5), and (2S)-N-hydroxy-2-(6-methoxy-2-naphthyl)propanamide (GUF-6) were synthesized as bioisosteres of the NSAIDs paracetamol, ibuprofen, and naproxen, respectively. All these compounds were characterized by spectroscopic and spectrometric analysis. Antinociceptive activity of GUF-1 to GUF-6 was evaluated using the formalin test in rats. Pharmacological responses of GUF-1, GUF-2 (hybrids), and GUF-5 (bioisostere) demonstrated significant antinociceptive effects; thus these compounds were assayed in an inflammation test like carrageenan-induced paw oedema in rats. Complete molecular docking of cyclooxygenase and the GUF-1 and GUF-2 hybrids showed high docking scores, compared to the reference drugs. Our data demonstrate that compounds GUF-1, GUF-2, and GUF-5 possesses antinociceptive and antiinflammatory activities resembling and improving those known for the traditional NSAIDs, paracetamol, naproxen and ibuprofen.

Synergistic antinociceptive interaction of Syzygium aromaticum or Rosmarinus officinalis coadministered with ketorolac in rats.

Syzygium aromaticum (L.) Merr. & L.M. Perry (Mirtaceae) and Rosmarinus officinalis L. (Lamiaceae) are both medicinal plants used for centuries to alleviate pain. The aim of the study was to demonstrate the therapeutic potential utility of herb-drug association of S. aromaticum essential oil or R. officinalis ethanolic extract coadministered with ketorolac. Antinociceptive pharmacological interaction was investigated by an isbolographic study using the formalin test in rats. Both alone and in combination with ketorolac; S. aromaticum and R. officinalis produced a dose-dependent antinociceptive response. To plot the isobologram, we used the effective dose 50 of each one component in a fixed 1:1 ratio. The isobolographic analysis showed that, in both combinations, ketorolac plus essential oil S. aromaticum and ketorolac plus ethanolic extract R. officinalis, the experimental value (Zexp) was lower than the theoretical value (Zadd). In addition, this study shows that eugenol, a metabolite present in S. aromaticum, and ursolic acid, a metabolite present in R. officinalis, also synergized the antinociceptive effect of ketorolac. While, the oleanolic acid present in both medicinal species did not show a synergistic antinociceptive effect in combination with ketorolac. No adverse effects were observed with these herb-drug interactions. These findings suggest that essential oil S. aromaticum and ethanolic extract R. officinalis could be useful in combination with ketorolac for the treatment of inflammatory pain.

Antihyperalgesic activity of a mexicanolide isolated from Swietenia humilis extract in nicotinamide-streptozotocin hyperglycemic mice.

Swietenia humilis Zucc. (Meliaceae) seeds are used in Mexico for the treatment of type 2 diabetes mellitus. Mexicanolides are the main hypoglycemic and antihyperglycemic compounds of the species. This study was conducted to investigate the antihyperalgesic effect of an aqueous extract of the seeds of Swietenia humilis (SHAE) and of mexicanolide 2-hydroxy-destigloyl-6-deoxyswietenine acetate (1), using the formalin test in mice. The antihyperalgesic actions of SHAE and mexicanolide 1, as well as its possible transductional activity, were assessed in nicotinamide-streptozotocin (NA-STZ) hyperglycemic mice. Local injection of SHAE (10-177µg) and mexicanolide 1 (0.5-3.5µg) exhibited concentration-dependent antihyperalgesic action in NA-STZ hyperglycemic mice. Ketanserin (6µg), a 5-HT2A/C receptor antagonist, and flumazenil (6µg), a GABAA receptor antagonist, abolished the antihyperalgesic effect of mexicanolide 1 (3µg). On the other hand, naloxone (3µg), L-arginine (50µg), and Nω-Nitro-l-arginine methyl ester hydrochloride (150µg) diminished the antihyperalgesic effect of mexicanolide 1. The aqueous extract of the seeds possesses significant antihyperalgesic action. Compound 1 produces antihyperalgesia through GABAA, 5-HT2A/C and opioid receptors. Also, the nitrergic system is involve in the antihyperalgesic effect of 1. Data obtained with Swietenia humilis Zucc. seeds give evidence of its potential for pain associated with diabetes treatment.

Antinociceptive pharmacological profile of Dysphania graveolens in mouse.

This work evaluates the potential antinociceptive activity of Dysphania graveolens, traditional medicinal plant used in Mexico to treat stomach pain. A CH2Cl2-MeOH extract, infusion and essential oil from aerial parts of Dysphania graveolens were evaluated in hot plate and writhing tests in mice. The metabolites pinostrobin, pinocembrin and chrysin were isolated from the Dysphania graveolens infusion; next, they were evaluated in both nociceptive tests. To confirm the antinociceptive activity and explore the possible participation of opioid, GABA and serotonin receptors in the pharmacological mechanism, a formalin test was used. Oral administration of Dysphania graveolens CH2Cl2-MeOH extract, infusion and essential oil (31-316mg/kg) produced an antinociceptive response to thermic and chemical algesic stimuli. Essential oil was the most active partition of this plant. In addition, the secondary metabolites pinostrobin, pinocembrin and chrysin possess a significant antinociceptive effect. This response was confirmed by the formalin test for the CH2Cl2-MeOH extract of Dysphania graveolens and chrysin. In both cases, the antinociceptive activity was reverted in the presence of naltrexone, flumazenil and bicuculline antagonists. The 5-HT2A/2C receptors did not participate in the antinociceptive response of this plant. The overall information tends to support the efficacy of Dysphania graveolens as an analgesic and its cultural use in abdominal pain.

Antinociceptive and Antihyperalgesic Activity of a Traditional Maya Herbal Preparation Composed of Pouteria Campechiana, Chrysophyllum Cainito, Citrus Limonum, and Annona Muricata.

Preclinical Research The purpose of this work was to assess the antinociceptive and antihyperalgesic properties of an herbal preparation, composed of four vegetal species: Pouteria campechiana (P. campechiana), Chrysophyllum cainito (C. cainito), Citrus limonum (C. limonum), and Annona muricata (A. muricata), that is commonly used in combination (PCCA) in traditional Mayan medicine for the treatment of diabetes and pain. An ethanolic extract of PCCA was prepared at a ratio of 1:1:1:1 for each plant. The systemic antinociceptive effect of PCCA extract (50-600 mg/kg, p.o.) was dose-dependent in the rat formalin (1%) producing 66% antinociceptive response at 400 mg/kg, p.o. A concentration-dependent antinociceptive effect of the PCCA extract (20-160 mg/paw) was also demonstrated in the rat capsaicin (0.2%) test. The PCCA extract (100-400 mg/kg, p.o.) had antihyperalgesic effects in alloxan diabetic rats. These findings demonstrate the antinociceptive and antihyperalgesic effects of PCCA and supports the use of the plant extracts in Mayan folk medicine. Drug Dev Res 78 : 91-97, 2017. © 2017 Wiley Periodicals, Inc.

Moringa oleifera, a species with potential analgesic and anti-inflammatory activities.

Moringa oleifera has long been used in large demand in folk medicine to treat pain. The present study was undertaken to examine the antinociceptive and anti-inflammatory spectrum of M. oleifera leaf extracts discriminating the constituents' nature by using different kind of experimental models in rats. Pharmacological evaluation of a non-polar and/or polar extracts at several doses (30-300mg/kg, p.o.) was explored through experimental nociception using formalin test, carrageenan-induced paw edema and arthritis with subcutaneous injection of collagen in rats. Basic morphology characterization was done by scanning electronic microscopy and laser scanning confocal microscopy. Not only polar (from 30 or 100mg/kg, p.o.) but also non-polar extract produced significant inhibition of the nociceptive behavior with major efficacy in the inflammatory response in different assessed experimental models. This antinociceptive activity involved constituents of different nature and depended on the intensity of the induced painful stimulus. Phytochemical analysis showed the presence of kaempferol-3-glucoside in the polar extract and fatty acids like chlorogenic acid, among others, in the non-polar extract. Data obtained with M. oleifera leaf extracts give evidence of its potential for pain treatment.

Spasmogenic and spasmolytic activities of Agastache mexicana ssp. mexicana and A. mexicana ssp. xolocotziana methanolic extracts on the guinea pig ileum.

ETHNOPHARMACOLOGICAL RELEVANCE: Agastache mexicana has been used in traditional medicine for relief of abdominal pain and treatment of other diseases. Two subspecies have been identified: A. mexicana ssp. mexicana (AMM) and A. mexicana ssp. xolocotziana (AMX) and both are used traditionally without distinction or in combination. AIM OF THE STUDY: To determine the effect of methanol extracts of A. mexicana ssp. mexicana and A. mexicana ssp. xolocotziana on gut motility and their possible mechanism of action. MATERIALS AND METHODS: The effect of AMM and AMX methanol extracts were tested on the spontaneous activity in the isolated guinea pig ileum and on tissues pre-contracted with KCl, electrical field stimulation (EFS) or ACh. In addition, the possible mechanism of action of each subspecies on gut motility was analyzed in the presence of hexametonium, indomethacin, L-NAME, verapamil, atropine or pyrylamine. A comparative chromatographic profile of these extracts was also done to indicate the most abundant flavonoids presents in methanol extracts of both subspecies. RESULTS: AMM, but not AMX, induced a contractile effect in the guinea pig ileum. This spasmogenic effect was partially inhibited by atropine, antagonist of muscarinic receptors; and pyrilamine, antagonist of H1 receptors. In contrast, AMX, but not AMM, diminished the contractions induced by KCl, EFS or ACh. The spasmolytic activity of AMX was partially inhibited by hexamethonium, ganglionic blocker; and indomethacin, inhibitor of the synthesis of prostaglandins; but not by L-NAME, inhibitor of nitric oxide synthase. In addition, AMX diminished the maximal contraction induced by CaCl2 in a calcium-free medium. Chromatographic analyses of these methanol extracts showed the presence of acacetin and tilanin in both. CONCLUSIONS: These results suggest that in folk medicine only AMX should be used as spasmolytic, and not in combination with AMM as traditionally occurs, due to the spasmogenic effects of the latter. In addition, activation of nicotinic receptors, prostaglandins and calcium channels, but not nitric oxide mechanisms, could be responsible for the spasmolytic activity of AMX. On the other hand, release of ACh and histamine could be involved in the spasmogenic effect induced by AMM. Acacetin and tilanin are present in methanol extracts of both subspecies and both flavonoids were more abundant in AMX than AMM. Our findings contribute to the validation of the traditional use of Agastache mexicana in relieving gastrointestinal disorders, but indicate that the subspecie that should be used for this effect is A. mexicana ssp. xolocotziana.

Antihyperalgesic Activity of Rhodiola rosea in a Diabetic Rat Model.

Preclinical Research Rhodiola rosea L. (Crassulaceae) is used for enhancing physical and mental performance. Recent studies demonstrated that R. rosea had anti-inflammatory activity in animal models, for example, carrageenan- and nystatin-induced edema in rats, possibly by inhibiting phospholipase A2 and cyclooxygenases-1 and -2. In addition, R. rosea had antinociceptive activity in thermal and chemical pain tests as well as mechanical hyperalgesia. The purpose of the present study was to assess the antihyperalgesic effect of an ethanol extract of Rhodiola rosea (R. rosea) in a diabetic rat model. Rats were administered a single dose of streptozotocin (STZ; 50 mg/kg, i.p.) and hyperalgesia was evaluated four weeks later. Formalin-evoked (0.5%) flinching was increased in diabetic rats compared with nondiabetic controls Systemic (1-100 mg/kg, i.p.) and local (0.1-10 mg/paw into the dorsal surface of the right hind paw) administration of R. rosea ethanol extract dose-dependently reduced formalin-induced hyperalgesia in diabetic rats. The antihyperalgesic effect of R. rosea was compared with gabapentin. These results suggest that R. rosea ethanol extract may have potential as a treatment for diabetic hyperalgesia.

Antinociceptive and hypoglycaemic evaluation of Conyza filaginoides (D.C.) Hieron Asteraceae.

OBJECTIVES: This work was undertaken to assess the antinociceptive and hypoglycaemic properties of a quantified extract of Conyza filaginoides (CFOE), as well as the antinociceptive potential of rutin, the main active compound of the plant, in normoglycaemic and/or hyperglycaemic mice (nicotinamide-streptozotocin, NA-STZ). METHODS: The antinociceptive effect of CFOE was evaluated using the writhing, hotplate and formalin tests in mice. Rutin was also examined with the formalin test. In addition, the antihyperalgesic effect of CFOE was evaluated in hyperglycaemic mice. The hypoglycaemic effect of CFOE was tested using an acute hypoglycaemic assay, and oral glucose and sucrose tests in normoglycaemic and hyperglycaemic mice. KEY FINDINGS: CFOE showed antinociceptive effect when tested in normoglycaemic mice in the writhing and hotplate tests (31.6-316 mg/kg). CFOE was also active in both normoglycaemic and hyperglycaemic mice in the formalin test (10-100 µg/paw) revealing its antihyperalgesic property. Rutin reduced the nociceptive behaviour in the formalin test; its mechanism of action seems to involve GABAergic and opioid pathways. CFOE possessed noted hypoglycaemic and antihyperglycaemic effects in normoglycaemic and hyperglycaemic mice (31.6-316 mg/kg). CONCLUSIONS: The antinociceptive, antihyperalgesic and hypoglycaemic effects of C. filaginoides found in this study support the contemporary uses of the plant in Mexican folk medicine.

Isobolographic analysis of the antinociceptive interaction between ursolic acid and diclofenac or tramadol in mice.

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.