Tramadol and M1 Bioavailability Induced by Metamizole Co-Administration in Donkeys (Equus asinus).

Our objective was to assess the pharmacokinetic characteristics of metamizole when administered together with tramadol in a single intravenous dose to donkeys. Ten male animals received 10 mg∙kg-1 of dipyrone associated with 2 mg∙kg-1 of tramadol (T2M10) and 25 mg∙kg-1 of dipyrone with 2 mg∙kg-1 of tramadol (T2M25). Venous blood samples were taken from groups to determine the pharmacokinetics after drug administration, using initial brief intervals that were followed by extended periods until 48 h. Restlessness and ataxia were observed in two animals in the T2M25 group. Analysis revealed prolonged detectability of tramadol, 4-methylamine antipyrine, 4-aminoantipyrine (up to 24 h), and O-desmethyltramadol (up to 12 h) after administration. Although metamizole and its metabolites showed no significant pharmacokinetic changes, tramadol and O-desmethyltramadol exhibited altered profiles, likely because of competition for the active sites of CYP450 enzymes. Importantly, the co-administration of metamizole increased the bioavailability of tramadol and O-desmethyltramadol in a dose-dependent manner, highlighting their potential interactions and emphasizing the need for further dose optimization in donkey analgesic therapies. In conclusion, metamizole co-administered with tramadol interferes with metabolism and this interference can change the frequency of drug administration and its analgesic efficacy.

Pharmacokinetics and pharmacodynamics of intravenous dexmedetomidine (2 µg∙kg-1) in dogs.

This study assessed the pharmacokinetics and pharmacodynamics of low-dose dexmedetomidine after IV bolus in dogs. Six healthy adult dogs (6.8 ± 3.0 kg) received dexmedetomidine (2 µg.kg-1 IV) over 2 min, using an infusion pump. Blood samples were collected totaling 5 h of monitoring. A validated UHPLC-MS/MS method was used to determine the plasma concentration of dexemedetomidine. For pharmacodynamics, HR, RR, oscillometric MBP, Grint END sedation score were evaluated at baseline (T0), every 3 min (T3 to T21), and after 30 (T30) and 60 (T60) minutes, with p < 0.05. T1/2 was 28.28 ± 6.14 min; the area under the curve was 467.44 ± 60.42 ng/mL/min. The total clearance was 5.46 ± 0.41 mL/min/kg, the Vdss was 146.19 ± 21.04 mL/kg, and the C max was 3.13 ± 1.15 ng/mL. HR (bpm) decreased significantly from T6 (79 ± 21) to T21 (78 ± 31) compared to T0 (116 ± 28). RR(mpm) decreased from T3 (43 ± 44) to T60 (41 ± 23), with T0 being 70 ± 48. The MBP (mmHg) increased at T18 (151 ± 34), T21 (152 ± 35), and T30 (140 ± 27), compared to T0 (111 ± 22). Sedation occurred at all times post-bolus, with a maximum peak at T12 (END 8 ± 6). The low dose of dexmedetomidine provided sedation in all animals, characterizing rapid metabolization and elimination. However, cardiovascular effects still may have negative repercussions in dogs with hemodynamic comorbidities, highlighting the caution and individualization of its use in certain patients.

Pharmacotherapeutic monitoring of dipyrone in northeastern Brazilian donkeys (Equus asinus).

This study aimed to monitor the effects of dipyrone following multiple administrations in northeastern donkeys. Ten castrated male donkeys, aged 6.4 ± 3 years and weighing 130.6 ± 9.8 kg, were administered dipyrone (25 mg/kg IV) every 12 h, resulting in six administrations (D1 to D6) per animal. Blood samples were collected over a 72 h monitoring period. A validated UHPLC-MS/MS method was employed to determine the plasma concentrations of the 4- methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA). The calculated pharmacokinetic variables of 4-MAA after D1 and D6 were, respectively: Cmax (µg/mL) = 163.60 ± 179.72 and 178.79 ± 196.94; T1/2beta (h) = 2.65 ± 0.65 and 3.37 ± 1.03; and AUC0-t (µg/mL × h) = 240.38 ± 130.87 and 373.52 ± 78.85. The same variables for 4-AA were: Cmax, (µg/mL) = 0.44 ± 0.27 and 0.90 ± 0.31, T1/2beta (h) = 14.77 ± 13.13 and 35.97 and AUC0-t (µg/mL × h) = 3.20 ± 0.43 and 27.73 ± 11.99. Concentrations of 4-MAA exceeded the minimum concentration required for 50% inhibition of cyclooxygenases 1 and 2. However, an accumulation of 4-AA, was observed. Further clinical studies are necessary to ascertain the implications of these findings on the pharmacodynamic response to dipyrone in northeastern donkeys.

Pseudobombax parvifolium Hydroalcoholic Bark Extract: Chemical Characterisation and Cytotoxic, Mutagenic, and Preclinical Aspects Associated with a Protective Effect on Oxidative Stress.

Plants have long been used in traditional medicine to treat illnesses. Nevertheless, their chemical diversity requires studies to establish the extract dosage and its safe use. Pseudobombax parvifolium, an endemic species of the Brazilian Caatinga biome, is commonly used in folk medicine, due to its anti-inflammatory properties related to cellular oxidative stress; however, its biological properties have scarcely been studied. In this study, we chemically characterized the P. parvifolium hydroalcoholic bark extract (EBHE) and evaluated its cytotoxic, mutagenic, and preclinical aspects, as well as its antioxidant effect. Our phytochemical analysis revealed a significative total polyphenol content and identified loliolide for the first time in this species. Cytotoxicity, mutagenicity, and acute oral and repeated dose indicated no toxic effects on cell culture, Drosophila melanogaster, and Wistar rat exposure to different EBHE concentrations, respectively. Furthermore, we observed a significant decrease in lipid peroxidation and a mild hypoglycemic and hypolipidemic effect with repeated oral dosing of EBHE. Although there were no significant changes in glutathione content, we did observe a significant increase in superoxide dismutase at a dose of 400 mg/kg and in glutathione peroxidase at doses of 100, 200, and 400 mg/kg. These findings suggest that EBHE has potential as a source of bioactive molecules, and it can be used safely in traditional medicine and in the development of herbal medicines for application in the public health system.

Antioxidant and Lipid-Lowering Effects of Buriti Oil (Mauritia flexuosa L.) Administered to Iron-Overloaded Rats.

The indiscriminate use of oral ferrous sulfate (FeSO4) doses induces significant oxidative damage to health. However, carotene-rich foods such as buriti oil can help the endogenous antioxidant defense and still maintain other body functions. This study aimed to assess the effects of buriti oil intake in iron-overloaded rats by FeSO4 administration. Buriti oil has ß-carotene (787.05 mg/kg), α-tocopherol (689.02 mg/kg), and a predominance of monounsaturated fatty acids (91.30 g/100 g). Wistar rats (n = 32) were subdivided into two control groups that were fed a diet containing either soybean or buriti oil; and two groups which received a high daily oral dose of FeSO4 (60 mg/kg body weight) and fed a diet containing either soybean (SFe) or buriti oil (Bfe). The somatic and hematological parameters, serum lipids, superoxide dismutase (SOD), and glutathione peroxidase (GPx) were determined after 17 days of iron overload. Somatic parameters were similar among groups. BFe showed a decrease in low-density lipoprotein (38.43%) and hemoglobin (7.51%); an increase in monocytes (50.98%), SOD activity in serum (87.16%), and liver (645.50%) hepatic GPx (1017.82%); and maintained serum GPx compared to SFe. Buriti oil showed systemic and hepatic antioxidant protection in iron-overloaded rats, which may be related to its high carotenoid, tocopherol, and fatty acid profile.

Pharmacokinetic profiles of the two major active metabolites of metamizole, 4-methylaminoantipyrine (MAA) and 4-aminoantipyrine (AA), after intravenous injection in cats.

This study aimed to determine the pharmacokinetic profile of two active metabolites of metamizole (dipyrone), N-methyl-4-aminoanthypyrine (MAA) and 4-aminoanthypyrine (AA), after intravenous administration in cats. Eight healthy mixed-breed cats were intravenously administered metamizole (25 mg/kg). Blood samples were collected at predetermined time points for up to 48 h after administration. Information on behavioral changes in the animals and adverse effects was collected. Plasma aliquots were processed and analyzed using the ultra-performance liquid chromatography tandem mass spectrometry technique. A validated UPLC-MS/MS method was used to characterize the pharmacokinetics of MAA and AA. Salivation was identified as an adverse clinical sign. The mean maximal plasma concentrations of MAA and AA were 29.31 ± 24.57 µg/mL and 1.69 ± 0.36 µg/mL, with half-lives of around 4.98 and 14 h, respectively. The area under the plasma concentration curve values were 28.54 ± 11.33 and 49.54 ± 11.38 h*µg/mL for MAA and AA, respectively. The plasma concentration of MAA was detectable for up to 24 h and was smaller than AA. AA was detectable for >48 h. Results suggest that metamizole is converted into active metabolites in cats. Further PK/PD and safety studies should be performed before defining the dose or administration intervals for clinical use.

Use and Applicability of Ozone Therapy in Clinical Practice in Dentistry: An Integrative Review

Ozone is a colorless gas with a characteristic odor present in nature in the form of trivalent oxygen. In 2015, the Federal Council of Dentistry (CFO/Brazil) approved the use of ozone therapy and in 2018 the Ministry of Health (MS/Brazil) approved the application of Ozone Therapy as a Complementary Integrative Practice in the Unified Health System. Therefore, the objective of this study was to verify the applicability of ozone therapy in dental practice. This is an integrative literature review whose search was performed in the Medline/Pubmed, LILACS, SciElo, and Google Scholar databases. Studies published in the last 5 years in English, Portuguese or Spanish were eligible. After the search, 312 titles were found and after exclusion of duplicates and analysis of abstracts and full text, 13 articles were included in this review. The literature reports the application of ozone therapy in several areas in the treatment of acute and chronic diseases. As a mechanism of action, ozone has a direct antimicrobial effect, immunoregulation, antioxidant defenses, analgesic, and vasodilator effects. In dentistry, its applicability is mainly in preventive dentistry and as a complement in surgical procedur es, endodontic, and periodontal treatments.

El ozono es un gas incoloro de olor característico presente en la naturaleza en forma de oxígeno trivalente. En 2015, el Consejo Federal de Odontología (CFO) aprobó el uso de la ozonoterapia y en 2018 el Ministerio de Salud aprobó la aplicación de la Ozonoterapia como Práctica Integrativa Complementaria en el Sistema Único de Salud. Por lo tanto, el objetivo de este estudio fue verificar la aplicabilidad de la ozonoterapia en la práctica odontológica. Esta es una revisión integrativa de la literatura cuya búsqueda se realizó en las bases de datos Medline/Pubmed, LILACS, SciElo y Google Scholar. Fueron elegibles los estudios publicados en los últimos 5 años en inglés, portugués o español. Después de la búsqueda, se encontraron 312 títulos y después de la exclusión de duplicados y análisis de resúmenes y texto completo, se incluyeron 13 artículos en esta revisión. La literatura reporta la aplicación de la ozonoterapia en varias áreas en el tratamiento de enfermedades agudas y crónicas. Como mecanismo de acción, el ozono tiene un efecto antimicrobiano directo, de inmunorregulación, defensas antioxidantes, efectos analgésicos y vasodilatadores. En odontología su aplicabilidad es principalmente en odontología preventiva y como complemento en procedimientos quirúrgicos, tratamientos endodónticos y periodontales.

Mass Spectrometric Identification of Licania rigida Benth Leaf Extracts and Evaluation of Their Therapeutic Effects on Lipopolysaccharide-Induced Inflammatory Response.

Licania rigida Benth has been evaluated as an alternative drug to treat diseases associated with inflammatory processes. This study evaluated the anti-inflammatory effects of aqueous and hydroalcoholic leaf extracts of L. rigida with inflammation induced by lipopolysaccharides in in vitro and in vivo inflammation models. The phytochemical profile of the extracts, analyzed by ultra-fast liquid chromatography coupled with tandem mass spectrometry, revealed the presence of gallic and ellagic acids in both extracts, whereas isovitexin, ferulate, bulky amino acids (e.g., phenylalanine), pheophorbide, lactic acid, and pyridoxine were detected in the hydroalcoholic extract. The extracts displayed the ability to modulate in vitro and in vivo inflammatory responses, reducing approximately 50% of pro-inflammatory cytokine secretion (TNF-α, IL-1ß, and IL-6), and inhibiting both NO production and leukocyte migration by approximately 30 and 40% at 100 and 500 µg/mL, respectively. Overall, the results highlight and identify, for the first time, the ability of L. rigida leaf extract to modulate inflammatory processes. These data suggest that the leaf extracts of this plant have potential in the development of herbal formulations for the treatment of inflammation.

Antioxidant Effect of Coenzyme Q10 in the Prevention of Oxidative Stress in Arsenic-Treated CHO-K1 Cells and Possible Participation of Zinc as a Pro-Oxidant Agent.

Oxidative stress is an imbalance between levels of reactive oxygen species (ROS) and antioxidant enzymes. Compounds with antioxidant properties, such as coenzyme Q10 (CoQ10), can reduce cellular imbalance caused by an increase in ROS. CoQ10 participates in modulating redox homeostasis due to its antioxidant activity and its preserving mitochondrial functions. Thus, the present study demonstrated the protective effects of CoQ10 against oxidative stress and cytotoxicity induced by arsenic (As). Antioxidant capacity, formation of hydroperoxides, generation of ROS, and the effect on cellular viability of CoQ10, were investigated to determine the protective effect of CoQ10 against As and pro-oxidant compounds, such as zinc. Cell viability assays showed that CoQ10 is cytoprotective under cellular stress conditions, with potent antioxidant activity, regardless of the concentration tested. Zn, when used at higher concentrations, can increase ROS and show a pro-oxidant effect causing cell damage. The cytotoxic effect observed for As, Zn, or the combination of both could be prevented by CoQ10, without any decrease in its activity at cellular levels when combined with Zn.

Chemical Characterization of Flowers and Leaf Extracts Obtained from Turnera subulata and Their Immunomodulatory Effect on LPS-Activated RAW 264.7 Macrophages.

The anti-inflammatory properties of Turnera subulata have been evaluated as an alternative drug approach to treating several inflammatory processes. Accordingly, in this study, aqueous and hydroalcoholic extracts of T. subulata flowers and leaves were analyzed regarding their phytocomposition by ultrafast liquid chromatography coupled to mass spectrometry, and their anti-inflammatory properties were assessed by an in vitro inflammation model, using LPS-stimulated RAW-264.7 macrophages. The phytochemical profile indicated vitexin-2-O-rhamnoside as an important constituent in both extracts, while methoxyisoflavones, some bulky amino acids (e.g., tryptophan, tyrosine, phenylalanine), pheophorbides, and octadecatrienoic, stearidonic, and ferulic acids were detected in hydroalcoholic extracts. The extracts displayed the ability to modulate the in vitro inflammatory response by altering the secretion of proinflammatory (TNF-α, IL-1ß, and IL-6) and anti-inflammatory (IL-10) cytokines and inhibiting the PGE-2 and NO production. Overall, for the first time, putative compounds from T. subulata flowers and leaves were characterized, which can modulate the inflammatory process. Therefore, the data highlight this plant as an option to obtain extracts for phytotherapic formulations to treat and/or prevent chronic diseases.

Phenolic Composition, Toxicity Potential, and Antimicrobial Activity of Licania rigida Benth (Chrysobalanaceae) Leaf Extracts.

This study was conducted to evaluate the phenolic composition, toxicity, and antimicrobial activity of Licania rigida Benth, an underexploited wild Licania species. L. rigida leaf fractions (ethyl alcohol and ethyl acetate) were analyzed for their phenolic compound and flavonoid total, and high-performance liquid chromatography/ultraviolet spectra chromatographic profiles. Regarding the extract biological effects, toxicity was measured by acute oral toxicity in Wistar rats, MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] method, and apoptosis indicators with DAPI in VERO cells, whereas well-agar diffusion and broth microdilution assays were applied to evaluate the antimicrobial ability. The phytochemical analysis resulted in significant amounts of phenolic compounds and total flavonoids in the extract and fraction, with flavonol-3-O-glycosylates as the main constituent. Regarding the extract and fraction antimicrobial activity, the results showed a significant effect against gram-positive bacteria and fungi, among which Staphylococcus epidermidis and Candida krusei displayed more susceptibility. No toxicity effects were observed in animals. Concerning the cytotoxicity assay, only the highest dose tested exhibited a minimal toxic effect on the analyzed cell lines. These results are relevant considering the increase of multiresistant microorganisms to conventional treatments applied. Therefore, investigating the pharmacological properties of the genus Licania is promising in the search for new sources of antimicrobial compounds.

Licania rigida leaf extract: Protective effect on oxidative stress, associated with cytotoxic, mutagenic and preclinical aspects.

Brazilian plant biodiversity is a rich alternative source of bioactive compounds since plant-derived extracts and/or their secondary metabolites exhibit potential properties to treat several diseases. In this context, Licania rigida Benth (Chrysobalanaceae Family), a large evergreen tree distributed in Brazilian semi-arid regions, deserves attention for its widespread use in popular medicine, although its biological properties are still poorly studied. The aim of this study was to examine (1) acute and sub-chronic oral toxicity at 2000 mg/kg dose; (2) in vitro cytotoxicity at 0.1; 1; 10; 100 or 1000 µg/ml; (3) in vivo mutagenicity at 5, 10 or 20 mg/ml, and (4) potential antioxidant protective effect of L. rigida aqueous leaf extract of (AELr). No marked apparent toxic and genotoxic effects were observed using in vitro and in vivo assays after in vitro treatment of Chinese hamster ovary cell line (CHO-K1) with AELr or in vivo exposure of Wistar rats and Drosophila melanogaster to different extract concentrations. Concerning the antioxidant effect, the extract exhibited a protective effect by decreasing lipid peroxidation as determined by malondialdehyde levels. No significant changes were observed for glutathione (GSH) levels and activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Data demonstrate the beneficial potential of AELr to be employed for therapeutic purposes. However, further studies are required to validate the pharmacological application of this plant extract to develop as a phytotherapeutic formulation.

Pharmacokinetic properties of metamizole active metabolites in Northeastern Brazilian donkeys (Equus asinus).

Metamizole (MT), also known as dipyrone, is an analgesic and antipyretic drug labeled for use in humans and domestic animals in some countries. As with other drugs, the administration of MT in donkeys is based on studies carried out with horses. In the present report, we aimed to determine the pharmacokinetics of the two main metamizole active metabolites (N-methyl-4-aminoantipyrine [MAA] and 4-aminoantipyrine [AA]) following 10 (M10 ) and 25 mg/kg (M25 ) IV metamizole doses in Northeast Brazilian donkeys (n = 10). Blood was collected at predetermined times within over 48 h; MAA and AA plasma concentrations were determined by a validated LC-MS/MS method. The metabolites were quantifiable in the M10 until 12 h and M25 until 24 h after drug administration. As expected, AUC0→t , AUC0→∞, and Cmax demonstrated significant differences increases in metamizole metabolites profiles when groups were compared. No adverse effects were observed. This study indicates the need for an extremely sensitive analytical method to adequately characterize the pharmacokinetics of active metabolites of MT, MAA, and AA. In conclusion, the method developed in this research was able to measure the active metabolites of metamizole and with that it was possible to establish their pharmacokinetic profile. Furthermore, after projection of the minimum MAA concentrations, it is possible to infer that the dose of 10 mg/kg will be used on donkeys at 6 h intervals, while the M25 group at 12 h intervals. However, clinical studies are needed to assess this hypothesis.

Pharmacokinetic properties of tramadol and M1 metabolite in Northeast Brazilian donkeys (Equus asinus).

There is currently little information available on the pharmacokinetics and pharmacodynamics of the analgesic opioid tramadol when used in the veterinary medicine of domestic species. In this study, we aimed to determine the pharmacokinetics of tramadol and its active metabolite M1 following intravenous administration of 2 (T2) and 4 (T4) mg/kg to Northeast Brazilian donkeys. Tramadol and M1 plasma levels were quantified using a validated liquid chromatography-tandem mass spectrometry method. We found that plasma levels of tramadol and M1 were higher than those reported as clinically meaningful in humans for at least 3 hr. However, the pharmacokinetic parameter calculation corrected by dose analysis identified no proportional increase with dose for the AUC of tramadol (T2: 2,663 ± 1,827 vs. T4: 2,964 ± 1,038 ng*h/ml) and M1 (T2: 378 ± 237 vs. T4: 345 ± 142 ng*h/ml). This finding appears to be attributable to a significant increase in clearance and a reduction in the terminal half-life of tramadol. The frequency of adverse effects observed at the higher dose indicates that 2 mg/kg administered intravenously would be suitable for donkeys. Clinical studies are required to determine the implications of these observations regarding the pharmacodynamic response to tramadol in Northeast Brazilian donkeys.

Chemical composition, antioxidant activity and hepatoprotective potential of Rourea induta Planch. (Connaraceae) against CCl4-induced liver injury in female rats.

OBJECTIVES: The aim of this study was to evaluate the flavonoid content of an ethanolic leaf extract from the medicinal plant Rourea induta Planch. (RIEE) and to investigate its hepatoprotective potential and in vivo antioxidant effects. METHODS: Using samples from carbon tetrachloride-treated Wistar female rats treated orally with or without RIEE, we evaluated the aspartate aminotransferase, alanine aminotransferase, and total bilirubin levels in plasma; the levels of the hepatic oxidative stress markers catalase, superoxide dismutase, glutathione peroxidase, and reduced glutathione in liver homogenates; and the thiobarbituric acid reactive substance levels. A histopathology study was performed. A quantitative analysis of the RIEE extract was performed using high-performance liquid chromatography to evaluate its flavonoid content. RESULTS: Oral administration of RIEE significantly reduced carbon tetrachloride-induced elevations in the levels of plasma markers of hepatic damage and lipid peroxidation. It also rescued histopathologic alterations observed in the liver and levels of oxidative stress markers. CONCLUSIONS: RIEE exhibits antioxidant and hepatoprotective activities in vivo, which may be attributable to its flavonoids composition [hyperin (2), quercetin-3-O-ß-xyloside (4), quercetin-3-O-α-arabinofuranoside (5), and quercetin (6)].