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Scientific Reports Jul 2022Urolithin A (UA, 1), a gut microbiota postbiotic metabolite is attributed to express interesting biological activities indicated by in vitro, in vivo and clinical...
Urolithin A (UA, 1), a gut microbiota postbiotic metabolite is attributed to express interesting biological activities indicated by in vitro, in vivo and clinical studies. Due to its strong anti-inflammatory properties it is considered as a promising lead molecule for further drug development, however, its strong phase II metabolism, severely limits its oral application. Therefore, monoesterified UA derivatives with selected NSAIDs: ibuprofen (Mix 3a/3b), mefenamic acid (Mix 4a/4b), diclofenac (Mix 5a/5b) and aspirin (Mix 6a/6b) were designed. Performed array of stability assays indicated Mix 4a/4b as a most suitable candidate for further studies due to its exceptional stability in human plasma. Thus, we evaluated effects of Mix 4a/4b on cell viability as well as the impact on cytokines secretion in THP-1 derived macrophages and compared it to UA. At high concentration (50 µM) Mix 4a/4b expressed a cytotoxic effect, however at concentration of 5 µM it significantly suppressed TNF-α secretion, and significantly increased ani-inflammatory IL-10 secretion at 10 µM without affecting cell viability. This work has led to selection of a novel UA derivatives, which are stable in solutions and in human plasma as well as posess anti-inflammatory activity towards THP-1 macrophages at non-cytotoxic concentrations.
Topics: Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Coumarins; Humans; Ibuprofen
PubMed: 35804000
DOI: 10.1038/s41598-022-15870-8 -
Children (Basel, Switzerland) Jun 2022Mefenamic acid (MFA), a water-insoluble drug, is used as a suspension in the medical field, but it requires shaking before using to disperse MFA content in the...
Mefenamic acid (MFA), a water-insoluble drug, is used as a suspension in the medical field, but it requires shaking before using to disperse MFA content in the suspension. In previous studies, trials to prepare MFA suspension with high dispersion stability by atomizing MFA by the wet-milling method. However, HPC is used for atomizing MFA. Therefore, the optimum concentration and molecular weight for atomizing MFA have not been investigated. In this study, we investigated the optimum molecular weight and concentration of HPC for the micronization of MFA. As a result, MFA particles became fine particles by adding SDS, and the particle size was also smaller than that of HPC alone. In addition, the suspension with the highest dispersion stability can be obtained when a mixed solution of 1.0% HPC-SL and 0.12% SDS aqueous solution is used. Therefore, this study considers that the addition of SDS and 1.0% HPC-SL aqueous solution are optimal for improving the dispersion stability of the MFA suspension.
PubMed: 35740798
DOI: 10.3390/children9060861 -
ACS Omega May 2022Three polymorphic structures of mefenamic acid, which is a very popular drug, have been studied using quantum chemical methods. It has been shown that the...
Three polymorphic structures of mefenamic acid, which is a very popular drug, have been studied using quantum chemical methods. It has been shown that the centrosymmetric dimer formed due to two O-H···O hydrogen bonds is a complex building unit in all of the polymorphic structures under study. On the basis of an analysis of the pairwise interaction energies between molecules, the polymorphic forms and are classified as columnar-layered while the polymorphic form has a columnar structure. The stabilities of the three polymorphic forms of mefenamic acid under ambient conditions ( > > ) correlate with the degree of anisotropy of the interaction energies between columns (primary basic structural motifs) formed due to stacking interactions. The shear deformation modeling of strongly bound layers in all of the polymorphic structures has not revealed any possibility for deformation of the crystal structure. The construction of the shift energy profiles and calculation of the energy barriers for the displacement along the (100) crystallographic plane in the [100], [010], and [011] crystallographic directions make it possible to explain the experimental data obtained for commercially available polymorphic structure in a diamond anvil cell. The absence of any local minimum near the starting point on the shift energy profile and the extremely high energy barrier can be considered as criteria for the impossibility of a crystal structure deformation under pressure.
PubMed: 35664581
DOI: 10.1021/acsomega.1c06967 -
Asian Pacific Journal of Cancer... May 2022Antiangiogenic agents are commonly used for the management of many types of cancers. Flaxseed oil is a wealthy source of omega-3,omega-6, and lignans, and possesses...
BACKGROUND
Antiangiogenic agents are commonly used for the management of many types of cancers. Flaxseed oil is a wealthy source of omega-3,omega-6, and lignans, and possesses anticancerous and antioxidant activities.
OBJECTIVE
To investigate the antiangiogenic activity of flaxseed oil alone and in combination with mefenamic acid in a dose-response study.
METHODS
Oil was extracted from flaxseeds. The ex vivo rat aorta ring assay was used to screen the flaxseed oil alone and in combination with mefenamic acid for possible antiangiogenic activity. Also, the assay was used to determine the dose-response effect.An in vivo chick chorioallantoic membrane (CAM) assay was used to quantify the zone of inhibition of blood vessel by flaxseed oil.
RESULTS
The 200,100,50,25,12.5, and 6.25µg/ml of the flaxseed oil inhibited blood vessel growth with values of 91±0.42, 84±2.06,36±2.71, 21±2.15,23±1.56, and 5±0.93%, respectively, withan IC50 value of 45.695 µg/ml. These concentrations showed a dose-dependent inhibition of angiogenesis. At 200, 100, and 50 µg/ml of flaxseed oil in combination with 50 µg/ml of mefenamic acid inhibited blood vessel growth with inhibition percentages of 81.48±0.82,79.63±0.75, and 77.78±1.26, respectively, with an IC50 of 2.27 µg/ml. Also, these concentrations indicated a dose-dependent inhibition of angiogenesis. Flaxseed oil produced a significant inhibition zone of blood vessels in the CAM assay. The LD50 for flaxseed oil was 5.656g/kg.
CONCLUSION
Flaxseed oil alone and in combination with mefenamic acid exhibited antiangiogenic activity both in ex vivo and in vivo assays. At doses of 2.5, 1.25, 0.625, and 0.312 g/kg of flaxseed oil intraperitoneally injected into mice, no symptoms of toxicity or death of mice due to acute toxicity were observed. However, doses of 5 and 10 g/kg of oil resulted in the death of the majority of mice.
Topics: Angiogenesis Inhibitors; Animals; Chickens; Fatty Acids, Omega-3; Flax; Humans; Linseed Oil; Mefenamic Acid; Mice; Rats
PubMed: 35633556
DOI: 10.31557/APJCP.2022.23.5.1711 -
European Journal of Pharmaceutics and... Jul 2022Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro...
Drug solubility in intestinal fluid is a key parameter controlling absorption after the administration of a solid oral dosage form. To measure solubility in vitro simulated intestinal fluids have been developed, but there are multiple recipes and the optimum is unknown. This situation creates difficulties during drug discovery and development research. A recent study characterised sampled fasted intestinal fluids using a multidimensional approach to derive nine bioequivalent fasted intestinal media that covered over 90% of the compositional variability. These media have been applied in this study to examine the equilibrium solubility of twenty one exemplar drugs (naproxen, indomethacin, phenytoin, zafirlukast, piroxicam, ibuprofen, mefenamic acid, furosemide, aprepitant, carvedilol, tadalafil, dipyridamole, posaconazole, atazanavir, fenofibrate, felodipine, griseofulvin, probucol, paracetamol, acyclovir and carbamazepine) to determine if consistent solubility behaviour was present. The bioequivalent media provide in the majority of cases structured solubility behaviour that is consistent with physicochemical properties and previous solubility studies. For the acidic drugs (pKa < 6.3) solubility is controlled by media pH, the profile is identical and consistent and the lowest and highest pH media identify the lowest and highest solubility in over 70% of cases. For weakly acidic (pKa > 8), basic and neutral drugs solubility is controlled by a combination of media pH and total amphiphile concentration (TAC), a consistent solubility behaviour is evident but with variation related to individual drug interactions within the media. The lowest and highest pH × TAC media identify the lowest and highest solubility in over 78% of cases. A subset of the latter category consisting of neutral and drugs non-ionised in the media pH range have been identified with a very narrow solubility range, indicating that the impact of the simulated intestinal media on their solubility is minimal. Two drugs probucol and atazanavir exhibit unusual behaviour. The study indicates that the use of two appropriate bioequivalent fasted intestinal media from the nine will identify in vitro the maximum and minimum solubility boundaries for drugs and due to the media derivation this is probably applicable in vivo. These media could be applied during discovery and development activities to provide a solubility range, which would assist placement of the drug within the BCS/DCS and rationalise drug and formulation decisions.
Topics: Administration, Oral; Atazanavir Sulfate; Hydrogen-Ion Concentration; Intestinal Absorption; Pharmaceutical Preparations; Probucol; Solubility
PubMed: 35605926
DOI: 10.1016/j.ejpb.2022.05.010 -
International Journal of Molecular... Apr 2022A reactive metabolite of nonsteroidal anti-inflammatory drugs (NSAIDs), acyl-β-D-glucuronide (AG), covalently binds to endogenous proteins. The covalent adduct...
A reactive metabolite of nonsteroidal anti-inflammatory drugs (NSAIDs), acyl-β-D-glucuronide (AG), covalently binds to endogenous proteins. The covalent adduct formation of NSAIDs-AG may lead to the dysfunction of target proteins. Therefore, it is important to clarify the detailed characterization of the formation of covalent protein adducts of NSAID-AG. UDP-glucuronosyltransferase (UGT) catalyzes the conversion of NSAIDs to NSAIDs-AG. The aim of this study was to perform a quantitative analysis of the covalent adduct formation of NSAIDs-AG with UGT. Diclofenac-AG and ketoprofen-AG formed covalent adducts with organelle proteins. Next, the number of covalent adducts formed between NSAIDs-AG and UGT isoforms (UGT1A1, UGT1A9, UGT2B4, and UGT2B9) was determined. The capacity of diclofenac-AG to form covalent adducts with UGT1A9 or UGT2B7 was approximately 10 times higher than that of mefenamic acid-AG. The amounts of covalent adducts of AG of propionic acid derivative NSAIDs with UGT2B were higher than those with UGT1A. Stereoselectivity was observed upon covalent binding to UGT. A significant negative correlation between the half-lives of NSAIDs-AG in phosphate buffers and the amount of covalent adduct with UGT2B7 was observed, suggesting the more labile NSAID-AG forms higher irreversible bindings to UGT. This report provides comprehensive information on the covalent adduct formation of NSAIDs-AGs with UGT.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Diclofenac; Glucuronides; Glucuronosyltransferase; Microsomes, Liver; UDP-Glucuronosyltransferase 1A9; Uridine Diphosphate
PubMed: 35563116
DOI: 10.3390/ijms23094724 -
Frontiers in Chemistry 2022The present study discusses comparative structural features of fourteen multicomponent solids of two non-steroidal anti-inflammatory drugs, Niflumic and Mefenamic acids,...
The present study discusses comparative structural features of fourteen multicomponent solids of two non-steroidal anti-inflammatory drugs, Niflumic and Mefenamic acids, with amine and pyridine-based coformers. All the solids were structurally characterized through PXRD, SCXRD, DSC, and the monophasic nature of some of the solids was established through Rietveld refinement. The solid forms include salt, cocrystal, hydrate, and solvate. Except for two, all the solids reported here showed relatively higher solubility compared to the acids. The difference in pa and similarity in structural features of both the molecules enabled us to study the effect of Δpa on crystallization outcome systematically. The structures of all the solids are described through acid-pyridine synthon perspective.
PubMed: 35433637
DOI: 10.3389/fchem.2022.729608 -
The Journal of Physical Chemistry. A Apr 2022A fragmentation approach referred to as a simple overlapping region method for force matching (SORForM) is presented. SORForM is designed to enable efficient computation...
Fragmentation Method for Computing Quantum Mechanics and Molecular Mechanics Gradients for Force Matching: Validation with Hydration Free Energy Predictions Using Adaptive Force Matching.
A fragmentation approach referred to as a simple overlapping region method for force matching (SORForM) is presented. SORForM is designed to enable efficient computation of quantum mechanical (QM) forces for large molecules and is validated in the framework of adaptive force matching (AFM) to develop solute models in water. The SORForM method divides a molecule into overlapping QM regions with each region containing a gradient zone and a buffer zone. The buffer zone ensures that the atoms in the gradient zone have their surroundings unchanged with fragmentation. The performance of the method is validated with mefenamic acid and linalyl acetate by comparing the hydration free energies of AFM models developed with and without SORForM. The AFM hydration free energies are also compared with that of the experiments. The models developed with B3LYP-D3(BJ) and def2-TZVP are in excellent agreement with experiments. Our work shows that PBE-D3(BJ) provides less satisfactory results when compared to B3LYP-D3(BJ). The def2-TZVP basis set is found to greatly improve the agreement with experiments when compared to a double-zeta quality basis set.
Topics: Entropy; Molecular Dynamics Simulation; Quantum Theory; Thermodynamics; Water
PubMed: 35420821
DOI: 10.1021/acs.jpca.2c01615 -
The Journal of Headache and Pain Mar 2022Certain constituents in migraine food triggers and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit sulfotransferases (SULTs) that detoxify drugs/chemicals and...
BACKGROUND/AIM
Certain constituents in migraine food triggers and non-steroidal anti-inflammatory drugs (NSAIDs) inhibit sulfotransferases (SULTs) that detoxify drugs/chemicals and play role in the metabolism of neurotransmitters. We aimed to dissect SULT1A1 modulation of CSD susceptibility and behavior in an in vivo experimental model using hesperidin, a SULT1A1 inhibitor found in citrus fruits (known migraine triggers) and mefenamic acid (SULT1A1 inhibitor), an NSAID to simulate medication overuse.
METHODS
Hesperidin was used as SULT1A1 inhibitor found in citrus fruits, known migraine triggers and mefenamic acid (NSAID), another SULT1A1 inhibitor, was used to induce MO in rats. The groups were; 1) Hesperidin (ip) or its vehicle-DMSO (ip) 2) Chronic (4 weeks) mefenamic acid (ip) or its vehicle (ip) 3) Chronic mefenamic acid+hesperidin (ip) or DMSO (ip). CSD susceptibility was evaluated and behavioral testing was performed. SULT1A1 enzyme activity was measured in brain samples.
RESULTS
Single-dose of hesperidin neither changed CSD susceptibility nor resulted in any behavioral change. Chronic mefenamic acid exposure resulted in increased CSD susceptibility, mechanical-thermal hypersensitivity, increased head shake, grooming and freezing and decreased locomotion. Single dose hesperidin administration after chronic mefenamic acid exposure resulted in increased CSD susceptibility and mechanical-thermal hypersensitivity, increased freezing and decreased locomotion. SULT1A1 enzyme activity was lower in mefenamic acid and mefenamic acid+hesperidin groups compared to their vehicles.
CONCLUSION
Mefenamic acid and hesperidin have synergistic effect in modulating CSD susceptibility and pain behavior. Sulfotransferase inhibition may be the common mechanism by which food triggers and NSAIDs modulate migraine susceptibility. Further investigations regarding human provocation studies using hesperidin in migraine patients with medication overuse are needed.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Humans; Mefenamic Acid; Migraine Disorders; Prescription Drug Overuse; Rats; Sulfotransferases
PubMed: 35282834
DOI: 10.1186/s10194-022-01405-z -
Journal of Ethnopharmacology May 2022The species Lippia origanoides Kunth, popularly known as "salva-de-marajó", is used in Brazilian traditional "quilombola" communities to treat menstrual cramps and...
ETHNOPHARMACOLOGICAL RELEVANCE
The species Lippia origanoides Kunth, popularly known as "salva-de-marajó", is used in Brazilian traditional "quilombola" communities to treat menstrual cramps and uterine inflammation.
AIM OF THE STUDY
Evaluate the spasmolytic activity of Lippia origanoides essential oil (LOO) on experimental models of uterine conditions related to menstrual cramps and investigate its mechanism of action.
MATERIALS AND METHODS
Virgin rat-isolated uterus was mounted in the organ bath apparatus to evaluate the spasmolytic effect of LOO on basal tonus and contractions induced by carbachol, KCl, or oxytocin. We used pharmacological agents to verify the relaxation mechanism of LOO. The evaluation of uterine contractility in virgin rats, after treatment with LOO for three consecutive days, was carried out by the construction of a concentration-response curve with oxytocin or carbachol. The primary dysmenorrhea animal model was replicated with an injection of estradiol cypionate in female mice for three consecutive days, followed by intraperitoneal application of oxytocin.
RESULTS
LOO relaxed the rat uterus precontracted with 10 IU/mL oxytocin (logEC = 1.98 ± 0.07), 1 μM carbachol (logEC = 1.42 ± 0.07) or 60 mM KCl (logEC = 1.53 ± 0.05). It was also able relax uterus on spontaneous contractions (logEC = 0.41 ± 0.05). Preincubation with glibenclamide, propranolol, phentolamine or L-NAME in contractions induced by carbachol did not alter significantly the relaxing effect of LOO. However, in the presence of 4-aminopyridine, CsCl or tetraethylammonium there was a reduction of LOO potency, whereas the blockers methylene blue, ODQ, aminophylline and heparin potentiated the LOO relaxing effect. Preincubation with LOO in a Ca free medium at concentrations of 27 μg/mL or 81 μg/mL reduced the contraction induced by carbachol. The administration of LOO for 3 days did not alter uterus contractility. The treatment with LOO at 30 or 100 mg/kg intraperitoneally, or 100 mg/kg orally, inhibited writhing in female mice. The association of LOO at 10 mg/kg with nifedipine or mefenamic acid potentiated writhing inhibition in mice.
CONCLUSIONS
The essential oil of L. origanoides has tocolytic activity in rat isolated uterus pre-contracted with KCl, oxytocin, or carbachol. This effect is possibly related to the opening of potassium channels (K, K and K), cAMP increase, and diminution of intracellular Ca. This relaxant effect, probably, contributed to reduce the number of writhings in an animal model of dysmenorrhea being potentiated by nifedipine or mefenamic acid. Taken together, the results here presented indicate that this species has a pharmacological potential for the treatment of primary dysmenorrhea, supporting its use in folk medicine.
Topics: Animals; Calcium; Carbachol; Cyclic AMP; Dysmenorrhea; Female; Lippia; Mefenamic Acid; Muscle Contraction; Nifedipine; Oils, Volatile; Oxytocin; Potassium Channels; Potassium Chloride; Rats; Tocolytic Agents; Uterine Contraction; Uterus
PubMed: 35167934
DOI: 10.1016/j.jep.2022.115099