Background/Objectives: The work investigates the effect of the estragole complex encapsulated in beta-cyclodextrin (ES/β-CD) in modulating bacterial resistance, specifically in Staphylococcus aureus strains expressing NorA and MepA efflux pumps. Efflux pumps are mechanisms that bacteria use to resist antibiotics by expelling them from the cell. Methodology: Several compounds and antibiotics, such as ciprofloxacin and norfloxacin, were used to evaluate the antimicrobial activity and the ability of the ES/β-CD complex to reverse resistance. Methods: The study included scanning electron microscopy assays, minimum inhibitory concentration (MIC) determination, and efflux pump inhibition tests. Results: The ES/β-CD complex did not show significant direct antibacterial activity. However, it modulated the action of norfloxacin, decreasing the MIC when combined with this antibiotic in the 1199B (NorA) strain. These results suggest a potential for synergy but not a direct inhibition of efflux pumps. Conclusion: ES/β-CD can potentiate the efficacy of some antibiotics but does not directly act as an efflux pump inhibitor; it is more of an antibiotic potentiator than a direct solution to bacterial resistance. The molecular docking simulation data suggest its high affinity for forming the ES/β-CD complex. The pharmacokinetic predictions based on MPO suggest that the compound has moderate lipophilicity, highly effective cellular permeability, and low incidence of organic toxicity, pointing to a promising pharmacological principle with controlled daily oral dosing. Conclusions: These results indicate this complex’s possible and relevant association as an adjuvant in antibiotic therapy to reduce multidrug-resistant bacteria; however, new in vivo assays are necessary to confirm this effect.

Background/Objectives: This study evaluated the antinociceptive effect of the Ximenia americana L. bark extract (HEXA) and its primary component, caffeic acid (CA), through in vivo assays. Methods: The antinociceptive properties were assessed using abdominal writhing, hot plate, and Von Frey tests. Additionally, the study investigated the modulation of various pain signaling pathways using a pharmacological approach. Results: The results demonstrated that all doses of the HEXA significantly increased latency in the hot plate test, decreased the number of abdominal contortions, reduced hyperalgesia in the Von Frey test, and reduced both phases of the formalin test. Caffeic acid reduced licking time in the first phase of the formalin test at all doses, with the highest dose showing significant effects in the second phase. The HEXA potentially modulated α₂-adrenergic (52.99%), nitric oxide (57.77%), glutamatergic (33.66%), vanilloid (39.84%), cyclic guanosine monophosphate (56.11%), and K⁺ATP channel-dependent pathways (38.70%). Conversely, CA influenced the opioid, glutamatergic (53.60%), and vanilloid (34.42%) pathways while inhibiting nitric oxide (52.99%) and cyclic guanosine monophosphate (38.98%). Conclusions: HEXA and CA exhibit significant antinociceptive effects due to their potential interference in multiple pain signaling pathways. While the molecular targets remain to be fully investigated, HEXA and CA demonstrate significant potential for the development of new analgesic drugs.

Ximenia americana L. (Olacaceae) has traditionally been used in folk medicine in the African continent and Brazilian Northeast to treat diseases such as diarrhea, fever, wounds, and pain. This study evaluated the antinociceptive effect of the Ximenia americana L. bark extract (HEXA) and its primary component, caffeic acid (CA), through in vivo assays. The antinociceptive properties were assessed using abdominal writhing, hot plate, and Von Frey tests. Additionally, the study investigated the modulation of various pain signaling pathways using a pharmacological approach. The results demonstrated that all doses of the HEXA extract significantly increased latency in the hot plate test, decreased the number of abdominal contortions, reduced hyperalgesia in the Von Frey test, and inhibited both phases of the formalin test. Caffeic acid reduced licking time in the first phase of the formalin test at all doses, with the highest dose showing significant effects in the second phase. The HEXA extract potentially modulated α2-adrenergic, nitric oxide, glutamatergic, vanilloid, cyclic guanosine monophosphate, and K+-ATP channel-dependent pathways. Conversely, caffeic acid influenced the opioid, glutamatergic, and vanilloid pathways while inhibiting nitric oxide and cyclic guanosine monophosphate. HEXA and CA exhibit significant antinociceptive effects due to their potential interference in multiple pain signaling pathways. While the molecular targets remain to be fully investigated, HEXA and CA demonstrate significant potential for the development of new analgesic drugs.

(+)-Nootkatone (NTK) is a bioactive sesquiterpene with significant therapeutic potential, but its application is hindered by low aqueous solubility and physical instability. Inclusion complexation with βcyclodextrin (βCD) offers an effective strategy to overcome these biopharmaceutical limitations. The present study investigated the antinociceptive effects of isolated nootkatone and its β-cyclodextrin inclusion complex (NTK/βCD) in murine models of acute nociception. The NYK/βCD complex was obtained by solvent co-evaporation method, and the drug content was quantified at 43.37% by GC-FID. Animals received NTK and NTK/βCD orally at 10 mg/kg. Central nervous system (CNS) effects were assessed using the rotarod and open-field tests, while antinociceptive activity was evaluated through the acetic acid-induced abdominal writhing test (1% acetic acid) and the formalin test (2.5% formalin). Additional assessment of antinociceptive effects was conducted using the hot plate and tail-flick tests. To elucidate the involvement of specific pain-signaling pathways, the opioid, nitric oxide, vanilloid, glutamatergic, cyclic guanosine monophosphate (cGMP), α1- and α2-adrenergic, dopaminergic, and serotonergic pathways were examined. Administration of NTK and NTK/βCD (10 mg/kg) did not produce significant effects on the CNS. In the acetic acid-induced abdominal writhing test, NTK and NTK/βCD reduced the number of writhes by 90.21% and 84.78%, respectively. In the formalin test, reductions of 51.81% and 47.58% were observed during the first phase, while reductions of 81.82% and 74.29% were observed during the second phase. In the hot plate test, NTK and NTK/βCD increased response latency by 116.72% and 121.66%, respectively. In the tail-flick test, response latency increased by 79.87% and 100.55%, respectively. Crucially, as NTK/βCD exhibited a drug content of 43.37%, the 10 mg/kg dose supplied an effective active payload of only 4.34 mg/kg and showed antinociceptive efficacy statistically equivalent to 10 mg/kg of uncomplexed NTK. The findings indicate that NTK and NTK/βCD may exert antinociceptive effects through the opioid, nitric oxide, vanilloid, glutamatergic, cGMP, and α2-adrenergic signaling pathways. Collectively these results demonstrate that that NTK and NTK/βCD possess significant antinociceptive potential and that β-cyclodextrin inclusion significantly enhances the dose efficiency of nootkatone, enabling equivalent pain management at less than half the active ingredient dose, rendering them promising candidates for the development of alternative therapeutic strategies for pain management.

(+)-Nootkatone (NTK) is a bioactive sesquiterpene with significant therapeutic potential, but its application is hindered by low aqueous solubility and physical instability. Inclusion complexation with βcyclodextrin (βCD) offers an effective strategy to overcome these biopharmaceutical limitations. The present study investigated the antinociceptive effects of isolated nootkatone and its β-cyclodextrin inclusion complex (NTK/βCD) in murine models of acute nociception. The NYK/βCD complex was obtained by solvent co-evaporation method, and the drug content was quantified at 43.37% by GC-FID. Animals received NTK and NTK/βCD orally at 10 mg/kg. Central nervous system (CNS) effects were assessed using the rotarod and open-field tests, while antinociceptive activity was evaluated through the acetic acid-induced abdominal writhing test (1% acetic acid) and the formalin test (2.5% formalin). Additional assessment of antinociceptive effects was conducted using the hot plate and tail-flick tests. To elucidate the involvement of specific pain-signaling pathways, the opioid, nitric oxide, vanilloid, glutamatergic, cyclic guanosine monophosphate (cGMP), α1- and α2-adrenergic, dopaminergic, and serotonergic pathways were examined. Administration of NTK and NTK/βCD (10 mg/kg) did not produce significant effects on the CNS. In the acetic acid-induced abdominal writhing test, NTK and NTK/βCD reduced the number of writhes by 90.21% and 84.78%, respectively. In the formalin test, reductions of 51.81% and 47.58% were observed during the first phase, while reductions of 81.82% and 74.29% were observed during the second phase. In the hot plate test, NTK and NTK/βCD increased response latency by 116.72% and 121.66%, respectively. In the tail-flick test, response latency increased by 79.87% and 100.55%, respectively. Crucially, with an encapsulation efficiency of 43.37% resulting in a drug-loading content of approximately 8.63% (w/w), the 10 mg/kg dose of NTK/βCD supplied an actual active nootkatone payload of only 0.86 mg/kg and showed antinociceptive efficacy statistically equivalent to 10 mg/kg of uncomplexed NTK. The findings indicate that NTK and NTK/βCD may exert antinociceptive effects through the opioid, nitric oxide, vanilloid, glutamatergic, cGMP, and α2-adrenergic signaling pathways. Collectively, these results demonstrate that NTK and NTK/βCD possess significant antinociceptive potential and that β-cyclodextrin inclusion significantly enhances the pharmacological performance of nootkatone at the tested dose level, rendering them promising candidates for the development of alternative therapeutic strategies for pain management.