RESUMO
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 mgâkg-1 of dipyrone associated with 2 mgâkg-1 of tramadol (T2M10) and 25 mgâkg-1 of dipyrone with 2 mgâkg-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.
RESUMO
The World Health Organization reported that tuberculosis remains on the list of the top ten threats to public health worldwide. Among the main causes is the limited effectiveness of treatments due to the emergence of resistant strains of Mycobacterium tuberculosis. One of the main drug targets studied to combat M. tuberculosis is DNA gyrase, the only enzyme responsible for regulating DNA topology in this specie and considered essential in all bacteria. In this context, the present work tested the ability of 2824 anthraquinones retrieved from the PubChem database to act as competitive inhibitors through interaction with the ATP-binding pocket of DNA gyrase B of M. tuberculosis. Virtual screening results based on molecular docking identified 7122772 (N-(2-hydroxyethyl)-9,10-dioxoanthracene-2-sulfonamide) as the best-scored ligand. From this anthraquinone, a new derivative was designed harbouring an aminotriazole moiety, which exhibited higher binding energy calculated by molecular docking scoring and free energy calculation from molecular dynamics simulations. In addition, in these last analyses, this ligand showed to be stable in complex with the enzyme and further predictions indicated a low probability of cytotoxic and off-target effects, as well as an acceptable pharmacokinetic profile. Taken together, the presented results show a new synthetically accessible anthraquinone with promising potential to inhibit the GyrB of M. tuberculosis.
RESUMO
Vanillic acid is found at high concentrations in many plants used in traditional medicine. It has been associated with a variety of pharmacologic activities such as carcinogenesis inhibition, apoptosis and inflammation; however, it has become most popular for its pleasant creamy odor. Since there are few reports concerning the antinociceptive activity of this phenolic compound, the aim of this work was to study this activity in in vivo animal models. Vanillic acid was administered by the intraperitoneal route producing a dose-dependent inhibition of the acetic acid-induced writhing response (ED50: 9.3mg/kg). The antinociceptive activity was inhibited by the pretreatment with ondansetron and yohimbine, indicating that the serotoninergic and adrenergic systems could participate in the mechanism underlying the analgesic activity of vanillic acid. This compound was also demonstrated to interact with ASICs (Acid-sensing Ion Channels) as well as with TPRV1, TRPA1, and TRPM8 receptors in vivo. Furthermore, vanillic acid did not interfere with the locomotor function or motor coordination. The plasmatic phenolic content, analyzed by HPLC, showed that its t1/2 and AUC were 0.123h and 1.38µg·h/mL; respectively. In conclusion, vanillic acid might represent a potential therapeutic option for the treatment of pain.