RESUMO
The current work aims to generate novel Schiff bases by reacting substituted aldehydes with amine derivatives catalyzed by a natural acid. The developed compounds underwent diverse physicochemical analyses including liquid chromatography-mass spectrometry, Fourier transform infrared spectroscopy, scanning electron microscopy, 1H- and 13C-nuclear magnetic resonance, and X-ray diffraction. Furthermore, differential thermogravimetric, thermogravimetric, and differential thermal analysis techniques were employed in a nitrogen-free environment to determine kinetic parameters. These data were then used in model-free isoconversional methods (e.g., Friedman, Kissinger-Akahira-Sunose, and Flynn-Wall-Ozawa). The Schiff bases were evaluated for their in vitro and in silico α-amylase inhibitory activity. Schiff base-2 displayed the highest inhibition compared with the reference drug acarbose. In comprehensive MTT assay cytotoxicity investigations, both Schiff bases showed strong anticancer capabilities against the human lung cancer cell line (A549). Moreover, this study demonstrated effectiveness of synthetic compounds in screening Caenorhabditis elegans for anti-Alzheimer's and stress resistance properties. The simplicity of its biology allowed precise evaluation of the effect of compounds on neuronal function and stress response. This research enhances drug discovery efforts for Alzheimer's and stress-related disorders, potentially improving patient outcomes.
RESUMO
These toxicity studies aimed to assess the safety and tolerability of a novel intravenous diclofenac sodium (37.5 mg/mL) formulation containing povidone K12 (80 mg/mL) as the key excipient in Wistar rats. This formulation was tested at doses of 3, 7, and 15 mg/kg/day and was administered daily for 28 days by intravenous route. Toxicokinetic estimation revealed a dose-proportional increase in plasma exposure to diclofenac. The formulation was well tolerated in males; however, mortality was observed in females (2/15) at the highest dose (15 mg/kg/day). Adverse gastrointestinal events related to NSAIDS and a few other treatment-related effects on clinical and anatomic pathology were noted at the 15 mg/kg/day dose, which normalized at the end of the 2-week recovery period. In addition, the excipient povidone K12 was present in a higher amount than the approved Inactive Ingredient Database (IID) limit in the proposed novel formulation. It was qualified through a separate 28-day repeated dose toxicity study by intravenous route in Wistar rats. Povidone K12 was found to be well tolerated and safe up to a dose of 165 mg/kg/day. No treatment-related adverse effects were observed in this study. In conclusion, repeated administration of a novel intravenous formulation containing diclofenac sodium was found to be safe up to the dose of 7 mg/kg/day in female rats and 15 mg/kg/day in male rats.
RESUMO
Electrocardiographic evaluation is performed in rhesus monkeys to establish the cardiovascular safety of candidate molecules before progressing to clinical trials. These animals are usually immobilized chemically by ketamine (KTM) and tiletamine-zolazepam (TZ) to obtain a steady-state heart rate and to ensure adequate human safety. The present study aimed to evaluate the effect of these anesthetic regimens on different electrocardiographic parameters. Statistically significant lower HR and higher P-wave duration, RR, QRS, and QT intervals were observed in the KTM-anesthetized group in comparison to TZ-anesthetized animals. No significant changes were noticed in the PR interval and p-wave amplitude. Sex-based significance amongst these parameters was observed in male and female animals of TZ- and KTM-anesthetized groups. Regression analysis of four QTc formulas in TZ-anesthetized rhesus monkeys revealed that QTcNAK (Nakayama) better corrected the QT interval than QTcHAS (Hassimoto), QTcBZT (Bazett), and QTcFRD (Fridericia) formulas. QTcNAK exhibited the least correlation with the RR interval (slope closest to zero and r = .01) and displayed no statistical significance between male and female animals. These data will prove useful in the selection of anesthetic regimens for chemical restraint of rhesus monkeys in nonclinical safety evaluation studies.
Assuntos
Anestésicos , Ketamina , Animais , Humanos , Masculino , Feminino , Ketamina/toxicidade , Tiletamina/toxicidade , Macaca mulatta , Zolazepam/toxicidade , Estudos Retrospectivos , Anestésicos/toxicidade , Frequência CardíacaRESUMO
The current research involves the synthesis of a new Schiff base through the reaction between 2-chlorobenzaldehyde and 3,3'-dimethyl-[1,1'-biphenyl]-4,4'-diamine by using a natural acid catalyst and a synthesized compound physicochemically characterized by X-ray diffraction, Fourier transform infrared spectroscopy, 1H- and 13C-nuclear magnetic resonance, and liquid chromatography-mass spectrometry. Thermal studies were conducted using thermogravimetric, differential thermal analysis, and differential thermogravimetric curves. These curves were obtained in an inert nitrogen environment from ambient temperature to 1263 K using heating rates of 10, 15, and 20 K·min-1. Using thermocurve data, model-free isoconversional techniques such as Kissinger-Akahira-Sunose, Flynn-Wall-Ozawa, and Friedman are used to determine kinetic parameters. These parameters include activation energy, phonon frequency factor, activation enthalpy, activation entropy, and Gibb's free energy change. All of the results have been thoroughly investigated. The molecule's anti-inflammatory and antidiabetic properties were also examined. To learn more about the potential of the Schiff base and how successfully it can suppress the amylase enzyme, a molecular docking experiment was also conducted. For in silico research, the Swiss Absorption, Distribution, Metabolism, Excretion, and Toxicity algorithms were used to calculate the theoretical pharmacokinetic properties, oral bioavailability, toxic effects, and biological activities of the synthesized molecule. Moreover, the cytotoxicity tests against a human lung cancer cell line (A549) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay demonstrated that the synthesized Schiff base exhibited significant anticancer properties.
RESUMO
Rhesus monkeys are a non-rodent species employed in the preclinical safety evaluation of pharmaceuticals and biologics. These nonhuman primate species have been increasingly used in biomedical research because of the similarity in their ionic mechanisms of repolarization with humans. Heart rate and QT interval are two primary endpoints in determining the pro-arrhythmic risk of drugs. As heart rate and QT interval have an inverse relationship, any change in heart rate causes a subsequent change in QT interval. This warrants for calculation of a corrected QT interval. This study aimed to identify an appropriate formula that best corrected QT for change in heart rate. We employed seven formulas based on source-species type, clinical relevance, and requirements of various international regulatory guidelines. Data showed that corrected QT interval values varied drastically for different correction formulas. Equations were compared on their slope values based on QTc versus RR plots. The rank order of the slope for different formulas was (closest to farthest from zero) QTcNAK, QTcHAS, QTcBZT, QTcFRD, QTcVDW, QTcHDG, and QTcFRM. QTcNAK emerged to be the best correcting formula in this study. It showed the least correlation with the RR interval (r = -0.01) and displayed no significant difference amongst the sexes. As there is no universally recognized formula for preclinical use, the authors recommend developing a best-case scenario model for specific study designs and individual organizations. The data from this research will be helpful in deciding an appropriate QT correction formula for the safety assessment of new pharmaceuticals and biologics.
Assuntos
Ketamina , Síndrome do QT Longo , Animais , Humanos , Eletrocardiografia , Macaca mulatta , Ketamina/toxicidade , Frequência Cardíaca , Preparações Farmacêuticas , Síndrome do QT Longo/induzido quimicamenteRESUMO
BACKGROUND: Nonhuman primates are used for research purposes such as studying diseases and drug discovery and development programs. Various clinical pathology parameters are used as biomarkers of disease conditions in biomedical research. Detailed reports of these parameters are not available for Indian-origin rhesus macaques. To meet the increasing need for information, we conducted this study on 121 adult Indian rhesus macaques (57 wild-sourced and 64 inhouse animals, aged 3-7 years). A total of 18 hematology and 18 biochemistry parameters were evaluated and reported in this study. Data from these parameters were statistically evaluated for significance amongst inhouse and wild-born animals and for differences amongst sexes. The reference range was calculated according to C28-A3 guidelines for reporting reference intervals of clinical laboratory parameters. RESULTS: Source of the animals and sex appeared to have statistically significant effects on reference values and range. Wild-born animals reported higher WBC, platelets, neutrophils, RBC, hemoglobin, HCT, MCV, and total protein values in comparison to inhouse monkeys. Sex-based differences were observed for parameters such as RBCs, hemoglobin, HCT, creatinine, calcium, phosphorus, albumin, and total protein amongst others. CONCLUSIONS: Through this study, we have established a comprehensive data set of reference values and intervals for certain hematological and biochemical parameters which will help researchers in planning, conducting, and interpreting various aspects of biomedical research employing Indian-origin rhesus monkeys.