The present study was aimed to evaluate the effect of licofelone, a dual inhibitor of cycloxygenase1/2-5-lipoxygenase against indomethacin-induced gastric damage in rats and mice in order to assess the role of leukotrienes if any, in non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrointestinal inflammation. Acute pretreatment with licofelone reversed the indomethacin-induced gastric ulceration, neutrophil adhesion in mesentery venules, neutrophil count in blood, lipid peroxides and vascularity in the stomachs of mice and rats. Further, chronic pretreatment of licofelone also prevented indomethacin-induced gastric morphological changes and cellular infiltration in mesentery venules. Moreover, acute administration of indomethacin elevated leukotriene B4 levels in gastric mucosa, which was reversed by pretreatment with licofelone The results suggest that licofelone offered gastroprotection against NSAIDs-induced gastropathy through its effect on leukotrienes and by inhibiting extravasation of neutrophils.
Licofelone, a competitive inhibitor of cyclooxygenases 1 and 2 and 5-lipoxygenase enzyme, is under clinical evaluation for its effectiveness in the treatme
No abstract is provided for this article.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
A flow duration curve (FDC) is widely used for predicting water supply, hydropower, environmental flow, sediment load, and pollutant load. Among different methods of constructing an FDC, the entropy-based method, developed recently, is appealing because of its several desirable characteristics, such as simplicity, flexibility, and statistical basis. This method contains a parameter, called entropy parameter M, which constitutes the basis for constructing the FDC. Since M is related to the ratio of the average streamflow to the maximum streamflow which, in turn, is related to the drainage area, it may be possible to determine M a priori and construct an FDC for ungauged basins. This paper, therefore, analyzed the characteristics of M in both space and time using streamflow data from 73 gauging stations in the Brazos River basin, Texas, USA. Results showed that the M values were impacted by reservoir operation and possibly climate change. The values were fluctuating, but relatively stable, after the operation of the reservoirs. Parameter M was found to change inversely with the ratio of average streamflow to the maximum streamflow. When there was an extreme event, there occurred a jump in the M value. Further, spatially, M had a larger value if the drainage area was small.
Synthesis of N -thiophenyl ebselenamines and selenenyl sulphides as efficient radical-trapping and hydroperoxide-decomposing antioxidants, respectively has been described.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
The aromatic nucleophilic substitution (S N Ar) reactions of N ‐(2‐bromo‐3‐nitrobenzyl)aniline ( 18 ), N ‐(2‐bromo‐3‐nitrobenzyl)‐4‐methylaniline ( 19 ) and N ‐(2‐bromo‐3‐nitrobenzyl)‐4‐nitroaniline ( 20 ) with [ n BuSeNa] afford N ‐[2‐(butylselanyl)‐3‐nitrobenzyl]aniline ( 21 ), N ‐[2‐(butylselanyl)‐3‐nitrobenzyl]‐4‐methylaniline ( 22 ) and N ‐[2‐(butylselanyl)‐3‐nitrobenzyl]‐4‐nitroaniline ( 23 ), respectively. The bromination of 21 results in the formation of cyclic isoselenazolines 7‐nitro‐2‐phenyl‐2,3‐dihydrobenzisoselenazole ( 27 ) and 2‐(4‐bromophenyl)‐7‐nitro‐2,3‐dihydrobenzisoselenazole ( 28 ). The bromination of 22 affords isoselenazolines 2‐(4‐methylphenyl)‐7‐nitro‐2,3‐dihydrobenzisoselenazole ( 29 ) and 2‐(2‐bromo‐4‐methylphenyl)‐7‐nitro‐2,3‐dihydrobenzisoselenazole ( 30 ) along with some other products. The bromination of 23 under identical conditions gave 2‐(2‐bromo‐4‐nitrophenyl)‐7‐nitro‐2,3‐dihydrobenzisoselenazole ( 31 ). The oxidation reaction of 21 – 22 with H 2 O 2 yielded isoselenazoline Se ‐oxides 7‐nitro‐2‐phenyl‐2,3‐dihydrobenzisoselenazole 1‐oxide ( 33 ) and 2‐(4‐methylphenyl)‐7‐nitro‐2‐phenyl‐2,3‐dihydrobenzisoselenazole 1‐oxide ( 34 ), respectively. The new isoselenazolines and isoselenazoline Se ‐oxides, stabilized by intramolecular secondary Se ··· O interactions, have been structurally characterized by single‐crystal X‐ray diffraction studies and investigated by computational studies. In addition to the synthesis and characterization, the glutathione peroxidase (GPx)‐like activities of isoselenazolines and isoselenazoline Se ‐oxides have been evaluated by coupled reductase assays.
Drug combinations have the potential advantage of greater analgesia over monotherapy. The present study was aimed to assess any possible interaction (additive or potentiation) in the antinociceptive effects of etoricoxib; a novel cyclooxygenase-2 inhibitor, and tramadol; a typical opioid agonist when administered in combination against mechanical hyperalgesia induced by spinal cord injury in rats. The nature of interaction was analyzed using surface of synergistic interaction (SSI) analysis and an isobolographic analysis. Etoricoxib or tramadol when administered alone to rats, exhibited different antihyperalgesic potencies (ED50 etoricoxib: 0.58±0.19 mg/kg, po; ED50 tramadol: 9.85±0.57 mg/kg, po). However, both the drugs were found to be long acting against this model of hyperalgesia. Further, etoricoxib and tramadol were co-administered in fixed ratios of ED50 fractions. One combination (0.29/4.79 mg/kg, po: etoricoxib/tramadol) exhibited additivity and other three combinations (0.15/2.39, 0.08/1.19, and 0.04/0.59 mg/kg, po: etoricoxib/tramadol) resulted in potentiation when analyzed by SSI. The SSI was calculated from the total antihyperalgesic effect produced by the combination after the subtraction of the antihyperalgesic effect produced by each of the individual drug. In the isobolographic analysis, the experimental ED50 was found to be far below the line of additivity also indicating a significant (P <0.05) synergistic antihyperalgesic effect when etoricoxib and tramadol was co-administered to rats. The synergistic antihyperalgesic effect of etoricoxib and tramadol combination suggests that these combinations may have clinical utility in mechanical hyperalgesia associated with spinal injury.
Tellurobistocopherols 9-11 were prepared by lithiation of the corresponding bromotocopherols, reaction with tellurium tetrachloride and reductive workup. Compounds 9-11 quenched linoleic-acid-derived peroxyl radicals much more efficiently than α-tocopherol in a chlorobenzene/water two-phase system. N-Acetylcysteine or tris(2-carboxylethyl)phosphine as co-antioxidants in the aqueous phase could regenerate the tellurobistocopherols and increase their inhibition times. Antioxidant 11 inhibited peroxidation for 7-fold longer than that recorded with α-tocopherol. Thiol consumption in the aqueous phase was monitored and found to be inversely related to the inhibition time.
The synthesis of 1,3-benzoselenazoles was achieved by the reaction of corresponding bis[3-amino-N-(p-tolyl)benzamide-2-yl] diselenide, bis[3-amino-N-(4-methoxyphenyl)benzamide-2-yl] diselenide, and bis[3-amino-N-(4-(dimethylamino)phenyl) benzamide-2-yl] diselenide with aryl aldehydes. The 1,3-benzoselenazoles continued to exist as planar molecules due to the presence of secondary Se···O interactions as revealed by the single-crystal X-ray analysis. The presence of secondary Se···O interactions in 1,3-benzoselenazoles was confirmed using natural bond orbital (NBO) and atoms in molecules (AIM) calculations. Nucleus-independent chemical shift (NICS) values suggested the presence of aromatic character in a five-membered benzoselenazole heterocyclic ring. The glutathione peroxidase (GPx)-like antioxidant activity of all 1,3-benzoselenazoles was assessed using a thiophenol assay, exhibiting greater antioxidant activity than Ph2Se2 used as a reference. The most active catalyst carrying a strong electron-donating group (–NMe2) at the ortho-position to the benzoselenazole ring was further investigated at different concentrations of thiophenol, H2O2, and 1,3-benzoselenazoles as catalyst for determining their catalytic parameters. Moreover, the potential applications of all 1,3-benzoselenazoles against pancreatic lipase (PL) have been identified using in silico interactions between the active sites of the 1LPB protein as evaluated using a molecular docking study.
Dual inhibitors that block both cyclooxygenase (COX) and lipoxygenase (LOX) metabolic pathways of arachidonic acid are expected to possess clinical advantages over the selective inhibitors of COX enzyme. One of the most promising compounds belonging to this category is licofelone ([2,2 -dimethyl -6-(4-chloropheny-7-phenyl-2,3-dihydro- 1H-pyrrazoline-5-yl] acetic acid). Originally discovered by Merckle GmbH and developed by EuroAllaince, licofelone (IC50 COX=0.21 μM, IC50 5-LOX=0.18μM) possesses significant analgesic, anti-inflammatory, and antiasthmatic effects at doses that cause no gastrointestinal (GI) side effects. The pharmacodynamic profile of licofelone has been assessed and compared with widely used NSAIDs in different animal models. The ED50 value of licofelone is reported to be 11.22- 27.07 mg/kg, po and 39.5-55-8 mg/kg, po against carrageenan-induced paw oedema and Randal Selitto hyperalgesic assay in rats, respectively. Licofelone showed analgesic effect (ED50 = 31.33 mg/kg) against acetic acid-induced writhing in mice. Licofelone has long duration of action and more effective than indomethacin and zileuton with ED50 values of 2.92 mg/kg, po and 36.77 mg/kg, po, in the mechanical hyperalgesia and cold allodynia testing, respectively, against rat model of incisional pain. Licofelone significantly ameliorated indomethacin-induced gastric ulceration, neutrophil adhesion in mesentery, and lipid peroxides in rat gastric mucosa. Also, licofelone reversed the altered vascular permeability, morphological changes, and prevented NSAIDs-related increase in leukotriene levels in gastric mucosa. The preclinical studies have shown that licofelone not only has convincing pharmacodynamic effect but also it is well tolerated. It is currently under clinical evaluation in osteoarthritis (OA), the most common form of arthritis. The present review describes pharmacological and clinical development of licofelone as a dual inhibitor. Keywords: COX-2 inhibitors, 5-LOX pathway, NSAIDs-induced gastrointestinal damage, PGH synthase, Licofelone
Singlet fission is a process by which two molecular triplet excitons are generated subsequent to the absorption of one photon. Molecules that enable singlet fission have triplet state energy at least half of the bright singlet state energy. This stringent energy criteria have challenged chemists to device new molecular and supramolecular design principles to modulate the singlet-triplet energy gap and build singlet fission systems from a wide range of organic chromophores. Herein, we report for the first time intramolecular singlet fission in the seminal naphthalenediimide (NDI) scaffold constrained in a push-pull cyclophane architecture, while individually the NDI chromophore does not satisfy the energy criterion. The challenging synthesis of this highly contorted push-pull cyclophane is possible from the preorganized pincer-like precursor. The special architecture establishes the shortest co-facial NDI⋯NDI contacts (3.084 Å) realized to date. Using broadband femtosecond transient absorption, we find that the correlated T-T pair forms rapidly within 380 fs of photoexcitation. Electronic structure calculations at the level of state-averaged CASSCF (ne,mo)/XMCQDPT2 support the existence of the multi-excitonic T-T pair state, thereby confirming the first example of singlet exciton fission in a NDI scaffold.
