Tolfenamic Acid Research Articles

Assessment of multiclass pharmaceutical active compounds (PhACs) in hospital WWTP influent and effluent samples by UHPLC-Orbitrap MS: Temporal variation, removals and environmental risk assessment

Nowadays the occurrence and associated risks of Pharmaceutical Active Compounds (PhACs) in the aquatic environment comprises a major issue. In the present study, a comprehensive survey on contamination profiles, occurrence, removals, temporal variation and ecological risk of multiclass multiresidue PhACs, such as antibiotics, non-steroidal anti-inflammatories, lipid regulators and phsychiatrics, (including past and newly monitored PhACs as well as some of their metabolites) was performed in wastewaters from the WWTP of Ioannina University hospital along one year period on a monthly sampling basis. WWTP influent and effluent samples were analyzed for physicochemical quality parameters and PhACs concentration levels using Ultra High Performance Liquid Chromatography-Orbitrap-Mass Spectrometry (UHPLC-Orbitrap-MS), after Solid Phase Extraction (SPE) through Oasis HLB cartridges. Influent concentrations ranged between < LOQ (Limit of Quantification) for diclofenac and tolfenamic acid and 48586 ng/L for caffeine, while effluent concentrations between < LOQ for tolfenamic acid and simvastatin and 3361 ng/L for caffeine. Removal efficiencies ranged between −132.6% for venlafaxine and 100% for caffeine. Environmental risk assessment by means of Risk Quotient (RQ) for maximum and minimum concentration levels as well as optimized by the frequency of exceeding toxicity threshold values, RQf, was applied revealing that up to 12 PhACs posed acute toxicity (clofibric acid, fenofibrate, sulfadiazine, sulfamethoxazole, trimethoprim, amitryptiline, fluoxetine, fluvoxamine, norfluoxetine, sertraline, venlafaxine, caffeine) while up to 4 compounds exerted long-term toxicity (sulfamethoxazole, fluoxetine, sertraline, caffeine) at least for one of the studied organisms. Furthermore, mixture RQMEC/PNEC and RQSTU effect of multiple compounds showed high potential risks of the target groups in some cases, although some contaminants were not included due to lack of available data. Results can be used to prioritization of PhACs and their metabolites for surveillance in receiving water bodies as well as development of knowledge on toxicity and mechanism(s) of action.

Crystal structures of tolfenamic acid polymorphic forms I and II with precise hydrogen-atom positions for nuclear magnetic resonance studies.

The structures of tolfenamic acid [TFA; 2-(3-chloro-2-methyl-anilino)benzoic acid, C14H12ClNO2] polymorph forms I and II have been redetermined [compare Andersen et al. (1989 ▸). J. Chem. Soc., Perkin Trans. 2, pp. 1443-1447] with improved precision using high-resolution X-ray diffraction data and Hirshfield atom refinement in order to better define both hydrogen-atom locations and their associated bond lengths. Covalent bond lengths to hydrogen were found to be significantly longer throughout both structures, especially for the anilino H atom, which is involved in an important intra-molecular N-H⋯O hydrogen bond to the carb-oxy-lic acid group. This hydrogen bond is shown to clearly perturb the electron density around both oxygen atoms in the latter group. The extended structures of both polymorphs feature carb-oxy-lic acid inversion dimers. These structures provide an improved foundation for nuclear magnetic resonance studies in both solution and the solid state.

Bimetallic Europium and Terbium Complexes Containing Substituted Terpyridines and the NSAID Drug Tolfenamic Acid: Structural Differences, Luminescence Properties, and Theranostic Applications

A series of bioactive homobimetallic Eu(III) and Tb(III) complexes containing terpyridine derivatives (XTPY) and tolfenamic acid, as a nonsteroidal anti‐inflammatory drug (NSAID), were synthesized as cellular imaging and photocytotoxic agents. The Ln2‐dimers were interestingly showing varying solid‐state structures during the process of crystallization originated from (i) multiple coordination modes of the carboxylate group in tolfenamic acids, (ii) exchange reactions with coordinating triflate (CF3SO3–) counter anions, (iii) in situ generated hydroxyls (OH–) from basic solution and, more importantly, (iv) the non‐directionality and ionic bonding nature of lanthanide complexes. The proposed species identified in solution from the isolated complexes were broadly represented as [Ln2(XTPY)2(TFA)6] (1–6): [Eu2(TOTPY)2(TFA)6] (1), [Tb2(TOTPY)2(TFA)6] (2), [Eu2(FTPY)2(TFA)6] (3), [Tb2(FTPY)2(TFA)6] (4), [Eu2(TTPY)2(TFA)6] (5), and [Tb2(TTPY)2(TFA)6] (6), where TOTPY = 4'‐(p‐tolyl)‐2,2':6',2''‐terpyridine, FTPY = 4'‐(2‐Furanyl)‐2,2':6',2''‐terpyridine, TTPY = 4'‐(2‐Thienyl)‐2,2':6',2''‐terpyridine and TFA = tolfenamic acid. Various physicochemical and spectroscopic methods were applied to understand their structures, speciation, and optical properties. The crystal structure analysis of the complexes shows that complexes 1 and 2 are isostructural as [Ln2(TOTPY)2(TFA)4(CF3SO3)2], while 3 and 4 are isostructural as [Ln2(FTPY)2(TFA)4(µ2‐OH)](CF3SO3), and complex 5 crystallizes as [Eu2(STPY)2(TFA)6(H2O)2]. Their solid‐state structures display eight‐coordinated {LnN3O5} distorted square antiprismatic or nine‐coordinated {LnN3O6} distorted tricapped trigonal prismatic (TTP) geometry around each Ln(III) ion. The interactions of dimeric complexes with biological targets (DNA, BSA) were tested. The complexes exhibit good binding affinity to DNA (Kb ca. 105 m–1) and BSA (KBSA ca. 106 m–1) via possible partial intercalation or groove binding with XTPY/TFA ligands. Eu(III) and Tb(III) luminescence in these complexes are effectively sensitized through the reinforced dual sensitizing ligands (XTPY and TFA). The confocal fluorescence imaging studies of these probes in the HeLa and MCF‐7 cell lines were tested using the intrinsic red and green emission originates from Eu(ΙΙΙ) and Tb(ΙΙΙ). Fluorescence imaging studies displayed their sufficient uptake and distribution in the cytosol and nuclei. The complexes showed significant photocytotoxicity under 365 nm UV‐A light.

Synthesis, characterization, antioxidant and antidiabetic studies of Cu(II) and Zn(II) complexes of tolfenamic acid/mefenamic acid with 1-methylimidazole

Cu(II) and Zn(II) complexes of tolfenamic acid (tolf) and mefenamic acid (mef) with 1-methylimidazole (1-mdz) formulated as [Cu(tolf)2(1-mdz)2] (1) [Cu(mef)2(1-mdz)2]·H2O (2) and [Zn2(tolf)4(1-mdz)2] (3) were synthesized and characterized by elemental analysis, spectroscopic techniques and single crystal X-ray crystallography. The molecular structure of the Cu(II) complexes, [Cu(tolf)2(1-mdz)2] (1) and [Cu(mef)2(1-mdz)2]·H2O (2) revealed CuN2O4 distorted octahedral geometry while [Zn2(tolf)4(1-mdz)2] (3) crystallized as dinuclear with Zn2N2O8 form and the geometry around each Zn(II) ion is square pyramidal. EPR spectra of 1 and 2 confirmed paramagnetic character with exchange interaction index, G of 5.27 and 7.39 respectively. The g tensor value, g// < 2.3 for 1 and 2 indicate covalent character supported by their non-electrolytic nature (Molar conductivity, Ʌm, 11.30–15.65 µS cm−1). The scavenging and iron chelating potentials of the compounds were evaluated. The compounds exhibit good antioxidant activity and SOD-mimetic activity determined for the complexes is in the order 3 ˃ 2˃ 1, the IC50 values for 2 and 3 being <1.00 µM are positive antioxidant indices, and are comparable with that of the native bovine, Cu,Zn-SOD (IC50 = 0.48 µM). A dismal performance observed for the dose-dependent antidiabetic potentials against alpha-amylase and alpha-glucosidase is attributed to insufficient inhibition of the latter.

Effect of dose on the intravenous pharmacokinetics of tolfenamic acid in goats

The objective of this study was to determine the pharmacokinetics of tolfenamic acid (TA) following intravenous (IV) administration at doses of 2 and 4mg/kg in goats. In this study, six healthy goats were used. TA was administered intravenously to each goat at 2 and 4mg/kg doses in a cross-over pharmacokinetic design with a 15-day washout period. Plasma concentrations of TA were analyzed using the high performance liquid chromatography with ultraviolet detector, and pharmacokinetic parameters were assigned by noncompartmental analysis. Following IV administration at dose of 2mg/kg, area under the concentration-time curve (AUC0-∞ ), elimination half-life (t1/2ʎz ), total clearance (ClT ) and volume of distribution at steady state (Vdss ) were 6.64±0.81hr* µg/ml, 1.57±0.14hr, 0.30±0.04 Lh-1 kg-1 and 0.40±0.05L/kg, respectively. After the administration of TA at a dose of 4mg/kg showed prolonged t1/2ʎz , increased dose-normalized AUC0-∞ , and decreased ClT . In goats, TA at 4mg/kg dose can be administered wider dose intervals compared to the 2mg/kg dose. However, further studies are needed to determine the effect of different doses on the clinical efficacy of TA in goats.

Synthesis, Characterization and Analgesic Activity of Cadmium(II) Complex of Tolfenamic Acid

Tolfenamic acid is a member of fenamate group of non-steroidal anti-inflammatory drugs (NSAID). It is generally used to treat migraine. In recent studies, metal complexes of traditional drugs like, manganese(II) complex of tolfenamic acid and mefenamic acid; cobalt(II) and zinc(II) complexes of tolfenamic acid are reported to give better biological activities than their parent drugs. In this study, tolfenamic acid was complexed with a divalent metal, cadmium(II) to form the drug-metal complex. The peripheral and central analgesic activities of this complex were tested to find out the impact of complexation on the pharmacological activity of the drug. Cadmium nitrate tetrahydrate was used for the complexation reaction and Fourier transform infrared (FT-IR) spectroscopic technique was used to identify the drug-metal complexation. Writhing method and tail flick technique were used to test peripheral and central analgesic activities, respectively in Swiss albino mice model. Comparison of the data obtained for positive and negative controls with the drug metal complex revealed a statistically significant increase in analgesic activities. Extensive experimentation is underway for further development in order to achieve better activity and assess toxicity profiles.&#x0D; Dhaka Univ. J. Pharm. Sci. 19(1): 59-64, 2020 (June)

Repurposing Fenamic Acid Drugs To Combat Multidrug-Resistant Neisseria gonorrhoeae.

The rise of extensively drug-resistant and multidrug-resistant strains of Neisseria gonorrhoeae has occurred in parallel with the increasing demand for new drugs. However, the current methods of drug discovery are burdened with rigorous assessments and require more time than can be spared until gonococcal infections become difficult to control. To address this urgency, we utilized a drug-repurposing strategy and identified three clinically approved anthranilic acid drugs (tolfenamic acid, flufenamic acid, and meclofenamic acid) with potent antigonococcal activity, inhibiting 50% of the strains (MIC50) from 4 to 16 μg/ml. Furthermore, tolfenamic acid showed indifferent activity with antibiotics of choice for gonococcal infections, azithromycin and ceftriaxone, in checkerboard assays with a fractional inhibitory concentration index ranging from 0.75 to 1.5. Fenamic acids reduced a high inoculum of N. gonorrhoeae below the limit of detection within 12 h and exhibited a low frequency of resistance. Interestingly, the fenamic acids did not inhibit the growth of commensal Lactobacillus spp. that comprise the healthy female genital microbiota. Fenamic acids were also superior to ceftriaxone in reducing the burden of intracellular N. gonorrhoeae within infected endocervical cells by 99%. Furthermore, all three fenamic acids significantly reduced the expression of proinflammatory cytokines by infected endocervical cells. Finally, fenamic acids and other structurally related anthranilic acid derivatives were evaluated to ascertain a more in-depth structure-activity relationship (SAR) that revealed N-phenylanthranilic acid as a novel antigonorrheal scaffold. This SAR study will pave the road to repositioning more potent fenamic acids analogues against N. gonorrhoeae.

Tolfenamic acid inhibits GSK-3\u03b2 and PP2A mediated tau hyperphosphorylation in Alzheimer\u2019s disease models

Tolfenamic acid, a nonsteroidal anti-inflammatory drug, alleviated learning and memory deficits and decreased the expression of specificity protein 1 (SP1)-mediated cyclin-dependent kinase-5 (CDK5), a major protein kinase that regulates hyperphosphorylated tau, in Alzheimer’s disease (AD) transgenic mice. However, whether tolfenamic acid can regulate the major tau protein kinase, glycogen synthase kinase-3β (GSK-3β), or tau protein phosphatase, protein phosphatase 2A (PP2A), further inhibiting hyperphosphorylation of tau, remains unknown. To this end, tolfenamic acid was administered i.p. in a GSK-3β overactivation postnatal rat model and orally in mice after intracerebroventricular (ICV) injection of okadaic acid (OA) to develop a PP2A inhibition model. We used four behavioural experiments to evaluate memory function in ICV-OA mice. In this study, tolfenamic acid attenuated memory dysfunction. Tolfenamic acid decreased the expression of hyperphosphorylated tau in the brain by inhibiting GSK-3β activity, decreasing phosphorylated PP2A (Tyr307), and enhancing PP2A activity. Tolfenamic acid also increased wortmannin (WT) and GF-109203X (GFX) induced phosphorylation of GSK-3β (Ser9) and prevented OA-induced downregulation of PP2A activity in PC12 cells. Altogether, these results show that tolfenamic acid not only decreased SP1/CDK5-mediated tau phosphorylation, but also inhibited GSK-3β and PP2A-mediated tau hyperphosphorylation in AD models.

Validation of Multi-Residue Method for Quantification of Antibiotics and NSAIDs in Avian Scavengers by Using Small Amounts of Plasma in HPLC-MS-TOF.

Pharmaceuticals are still considered emerging pollutants affecting both aquatic and terrestrial ecosystems. Scavenging bird species may be exposed to veterinary drugs when they feed on livestock carcasses provided at supplementary feeding stations, as these are often stocked with ailing and/or recently medicated animals. Because those animals may be a source of several different pharmaceutical compounds, analytical methods to evaluate residue levels and exposure potential should enable detection and quantification of as many different compounds as possible, preferably from small sample volumes. Four different extraction methods were tested to conduct HPLC-MS-TOF analysis of some of the most common veterinary drugs used in livestock in Spain. The method deemed most viable was a simple extraction, using methanol and 100 µL of plasma, that allowed quantification of seven antibiotics (tetracycline, oxytetracycline, ciprofloxacin, enrofloxacin, nalidixic acid, trimethoprim, sulfadiazine) and five nonsteroidal anti-inflammatory drugs (NSAIDs) (meloxicam, flunixin, carprofen, tolfenamic acid, phenylbutazone). The method was then applied to analysis of 29 Eurasian griffon vulture (Gyps fulvus) nestling samples, wherein enrofloxacin and tolfenamic acid were most commonly detected (69% and 20%, respectively). To our knowledge, this is the first study including NSAIDs in the exposure assessment of different classes of veterinary pharmaceuticals in live avian scavengers.

Structural and antibacterial properties of NSAID-loaded ultra-high molecular weight polyethylene

Peri-articular delivery of pain medication in joint arthroplasty has the potential to address post-operative pain and decrease the use of systemic opioids. Additionally, the sustained release from a delivery vehicle may be especially impactful in the initial post-operative period when pain is most severe. We recently described a novel approach for the sustained intra-articular delivery of an analgesic (bupivacaine) from an ultra-high molecular weight polyethylene (UHMWPE) bearing surface. A secondary but very significant effect of incorporating bupivacaine in UHMWPE was its antibacterial effect against Staphylococcal species, which are associated with the majority of periprosthetic joint infections. Here, we report on the structure, properties, elution characteristics and antibacterial properties of UHMWPE loaded with the non-steroidal anti-inflammatory drug (NSAID) — tolfenamic acid. We showed that 6 wt% drug loading was optimal for eluting clinically relevant intra-articular and systemic concentrations, for maintaining mechanical properties at a clinically relevant level, and for providing anti-colonization potential against low risk (planktonic) and high risk (biofilm forming) Staphylococcal species. We determined the osteoblast response to the tolfenamic acid-loaded UHMWPE to evaluate the cytotoxicity profile of this novel material. Tolfenamic acid-loaded UHMWPE has the potential to be used as a part of multimodal pain management therapy following arthroplasty and may provide prophylaxis for periprosthetic infection.

Development and validation of a spectrofluorimetric method for the analysis of tolfenamic acid in pure and tablet dosage form.

Tolfenamic acid (TA) is commonly used in humans and animals because of its anti-inflammatory, antipyretic, and analgesic effects. So far, no study has been carried out to develop a validated spectrofluorimetric method for determination of TA. Therefore, the present study aimed to develop and validate a simple, accurate, rapid, economical, and precise spectrofluorimetric method to assay TA in its pure and dosage forms, and also in degraded solutions. The fluorimetric method had higher sensitivity compared with the spectrophotometric and high-performance liquid chromatography methods and could determine the drug at the microgram level. Optimum pH of TA for maximum fluorescence intensity was 3, and its two pKa values were calculated as 1.95 and 4.05. The proposed method was validated according to the guidelines of the International Council for Harmonisation, and parameters such as linearity, range, accuracy, precision, sensitivity, robustness, specificity, and solution stability were tested. Stress-induced degradation studies on TA did not affect the accuracy and precision of the proposed method. The results obtained indicated that the method was linear over the concentration range 0.2-0.9 × 10-3 M with good accuracy, precision, and robustness for assay of TA in its pure and its tablet dosage forms and was comparable statistically with the British Pharmacopoeia method.

Combination use of tolfenamic acid with curcumin improves anti-inflammatory activity and reduces toxicity in mice.

Long-term use of tolfenamic acid inevitably causes side effects, including gastric ulcer and hepatotoxicity. Curcumin is generally recognized to be anti-inflammatory, hepatoprotective, and gastroprotective. Herein, we investigated the combinational effects of tolfenamic acid and curcumin and possible mechanism in a TPA-induced inflammation mouse model. Combinational use of tolfenamic acid (100mg/kg) and curcumin (100mg/kg) by oral administration reduced dermal inflammation represented by ear edema and lymphocytic infiltration. Moreover, curcumin dispersed in polyvinyl pyrrolidone showed stronger synergistic effect. The beneficial effect of the coadministration was also reproduced in PKC/Akt/IKK/NF-κB signaling pathways. Notably, hepatoprotective and gastroprotective effect was exhibited by the reverse of body weight loss and NF-κB downregulation in the liver, and by increased Spleen Index of mice. These results suggested combination administration of tolfenamic acid with curcumin enhances anti-inflammatory efficacy and reduces hepatic/gastric toxicity, which indicates dietary uptake of curcumin may facilitate the function of tolfenamic acid. PRACTICAL APPLICATIONS: Curcumin, a representative polyphenolic compound, is one of the main constituents of dietary spice turmeric which has been widely consumed throughout the world, especially in Asia. The beneficial aspect of combination use of curcumin in enhancing anti-inflammatory effect and reducing hepatic/gastric toxicity of NSAID drug tolfenamic acid in mice has been explored. It might be anticipated as a potential naturally derived bioactive constituent in functional food and pharmaceutical applications.

Influences of tolfenamic acid and flunixin meglumine on the disposition kinetics of levofloxacin in sheep.

The pharmacokinetics of levofloxacin (4 mg/kg), administered both alone and in combination with tolfenamic acid (2 mg/kg) and flunixin meglumine (2.2 mg/kg), was established after intravenous administration in sheep. Plasma levofloxacin concentrations were assayed by high-performance liquid chromatography and analysed according to the two-compartment open model. Following the administration of levofloxacin alone, the mean distribution half-life, elimination half-life, total clearance, volume of distribution at steady state and area under the plasma concentration-time curve were 0.20 h, 1.82 h, 0.39 L/h/kg, 0.96 L/kg and 10.40 h × µg/mL, respectively. Tolfenamic acid and flunixin meglumine caused a slow elimination and increased plasma concentrations of levofloxacin in combination administration. Levofloxacin, with an alteration in the dosage regimen, can be used effectively with tolfenamic acid and flunixin meglumine for the therapy of infections and inflammatory conditions in sheep.

Assessment of unconventional antimicrobial compounds for the control of \u2018Candidatus Liberibacter asiaticus\u2019, the causative agent of citrus greening disease

In this study, newly identified small molecules were examined for efficacy against ‘Candidatus Liberibacter asiaticus’ in commercial groves of sweet orange (Citrus sinensis) and white grapefruit (Citrus paradisi) trees. We used benzbromarone and/or tolfenamic acid delivered by trunk injection. We evaluated safety and efficacy parameters by performing RNAseq of the citrus host responses, 16S rRNA gene sequencing to characterize citrus-associated microbial communities during treatment, and qRT-PCR as an indirect determination of ‘Ca. L. asiaticus’ viability. Analyses of the C. sinensis transcriptome indicated that each treatment consistently induced genes associated with normal metabolism and growth, without compromising tree viability or negatively affecting the indigenous citrus-associated microbiota. It was found that treatment-associated reduction in ‘Ca. L. asiaticus’ was positively correlated with the proliferation of several core taxa related with citrus health. No symptoms of phytotoxicity were observed in any of the treated trees. Trials were also performed in commercial groves to examine the effect of each treatment on fruit productivity, juice quality and efficacy against ‘Ca. L. asiaticus’. Increased fruit production (15%) was observed in C. paradisi following twelve months of treatment with benzbromarone and tolfenamic acid. These results were positively correlated with decreased ‘Ca. L. asiaticus’ transcriptional activity in root samples.

Fenamates Inhibit Human Sodium Channel Nav1.2 and Protect Glutamate-Induced Injury in SH-SY5Y Cells

Voltage-gated sodium channels are crucial mediators of neuronal damage in ischemic and excitotoxicity disease models. Fenamates have been reported to have anti-inflammatory properties following a decrease in prostaglandin synthesis. Several researches showed that fenamates appear to be ion channel modulators and potential neuroprotectants. In this study, the neuroprotective effects of tolfenamic acid, flufenamic acid, and mefenamic acid were tested by glutamate-induced injury in SH-SY5Y cells. Following this, fenamates' effects were examined on both the expression level and the function of hNav1.1 and hNav1.2, which were closely associated with neuroprotection, using Western blot and patch clamp. Finally, the effect of fenamates on the expression of apoptosis-related proteins in SH-SY5Y cells was examined. The results showed that both flufenamic acid and mefenamic acid exhibited neuroprotective effects against glutamate-induced injury in SH-SY5Y cells. They inhibited peak currents of both hNav1.1 and hNav1.2. However, fenamates exhibited decreased inhibitory effects on hNav1.1 when compared to hNav1.2. Correspondingly, the inhibitory effect of fenamates was found to be consistent with the level of neuroprotective effects in vitro. Fenamates inhibited glutamate-induced apoptosis through the modulation of the Bcl-2/Bax-dependent cell death pathways. Taken together, Nav1.2 might play a part in fenamates' neuroprotection mechanism. Nav1.2 and NMDAR might take part in the neuroprotection mechanism of the fenamates. The fenamates inhibited glutamate-induced apoptosis through modulation of the Bcl-2/Bax-dependent cell death pathways.

Method Optimization: Analysis of Benzbromarone and Tolfenamic Acid in Citrus Tissues and Soil Using Liquid Chromatography Coupled With Triple-Quadrupole Mass Spectrometry

Herein, an analytical method was developed for extraction and quantification of benzbromarone and tolfenamic acid in citrus and soil matrices using liquid-liquid extraction followed by liquid chromatography-triple quadrupole-tandem mass spectrometry analysis. The compounds were extracted using 0.1% formic acid in 6:4 ethyl acetate and n-hexane solution, and the analytes were separated using a mixture of 0.1% formic acid in ultrapure water and 0.1% formic acid in acetonitrile as mobile phase. A six-point in-matrix calibration curve was constructed providing good linearity with coefficients of determination R2 ≥ 0.98. The limits of detection and quantification for benzbromarone and tolfenamic acid were 3.0 and 10.0 μg/kg in roots, peel, juice, and soil, and 4.0 and 12.0 μg/kg for leaves samples, respectively. The method yielded excellent recoveries between 81.3 and 101.2%, with relative standard deviation ≤9.5% in the matrices. The developed technique provides a simple and sensitive method for the determination of the chemicals and can be applied to agricultural practices.

Evaluation of Tolfenamic Acid in Individuals With PSP at 12-Weeks

Evaluation of Tolfenamic Acid in Individuals With PSP at 12-Weeks

Kinetic Difference between Concomitant Polymorphism and Solvent-Mediated Phase Transformation: A Case of Tolfenamic Acid

Detection of two or multiple polymorphs in solution is a result of concomitant polymorphism or due to solvent-mediated phase transition. In this work, crystallization of tolfenamic acid (TFA) was conducted under several different supersaturation and temperature conditions. Form I and form II were identified from crystallized samples. Solute concentration and polymorph composition were respectively determined by UV–vis and Raman spectroscopy through the course of crystallization. Kinetic modeling was also conducted to further examine the crystallization kinetics, revealing that the observed simultaneous nucleation of the two forms is characteristically associated with an intermediate recession of the relative amount of form I in crystal mixtures. This unambiguous kinetic event proves to be indicative of the concomitant crystallization of TFA, shedding light on its nucleation mechanism.

Isomorphism: 'molecular similarity to crystal structure similarity' in multicomponent forms of analgesic drugs tolfenamic and mefenamic acid.

The non-steroidal anti-inflammatory drugs mefenamic acid (MFA) and tolfenamic acid (TFA) have a close resemblance in their molecular scaffold, whereby a methyl group in MFA is substituted by a chloro group in TFA. The present study demonstrates the isomorphous nature of these compounds in a series of their multicomponent solids. Furthermore, the unique nature of MFA and TFA has been demonstrated while excavating their alternate solid forms in that, by varying the drug (MFA or TFA) to coformer [4-di-methyl-amino-pyridine (DMAP)] stoichiometric ratio, both drugs have produced three different types of multicomponent crystals, viz. salt (1:1; API to coformer ratio), salt hydrate (1:1:1) and cocrystal salt (2:1). Interestingly, as anticipated from the close similarity of TFA and MFA structures, these multicomponent solids have shown an isomorphous relation. A thorough characterization and structural investigation of the new multicomponent forms of MFA and TFA revealed their similarity in terms of space group and structural packing with isomorphic nature among the pairs. Herein, the experimental results are generalized in a broader perspective for predictably identifying any possible new forms of comparable compounds by mapping their crystal structure landscapes. The utility of such an approach is evident from the identification of polymorph VI of TFA from hetero-seeding with isomorphous MFA form I from acetone-methanol (1:1) solution. That aside, a pseudopolymorph of TFA with di-methyl-formamide (DMF) was obtained, which also has some structural similarity to that of the solvate MFA:DMF. These new isostructural pairs are discussed in the context of solid form screening using structural landscape similarity.

Risk Factors for Esophageal Cancer, with an Emphasis on the Role of Specificity Protein Transcription Factors in Prognosis and Therapy.

Specificity protein (Sp) transcription factors regulate the expression of genes associated with several cellular processes and play a critical role in early development. Typically, Sp protein expression decreases with age in healthy adults. Research has shown that Sp proteins can impact the development and transformation of cancer cells and other oncogenic processes, including survival, proliferation, spread, and metastasis. Among the Sp proteins, Sp1, Sp3, and Sp4 have been the main targets of study as they are shown to be highly expressed in cancer cells compared to healthy cells. Increased levels of Sp1 are correlated with poor prognosis in some malignancies, including gastrointestinal cancers. In this review, we discuss the role of Sp transcription factors and examine their activities as pro-oncogenic factors in esophageal cancer (EC). Other aspects presented in this review are potential therapeutic options for EC that target Sp1. We summarize the published information on preclinical results using mithramycin and tolfenamic acid.