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Scientific Reports Jul 2022Accurate specification of the drugs' solubility is known as an important activity to appropriately manage the supercritical impregnation process. Over the last decades,...
Accurate specification of the drugs' solubility is known as an important activity to appropriately manage the supercritical impregnation process. Over the last decades, the application of supercritical fluids (SCFs), mainly CO, has found great interest as a promising solution to dominate the limitations of traditional methods including high toxicity, difficulty of control, high expense and low stability. Oxaprozin is an efficient off-patent nonsteroidal anti-inflammatory drug (NSAID), which is being extensively used for the pain management of patients suffering from chronic musculoskeletal disorders such as rheumatoid arthritis. In this paper, the prominent purpose of the authors is to predict and consequently optimize the solubility of Oxaprozin inside the COSCF. To do this, the authors employed two basic models and improved them with the Adaboost ensemble method. The base models include Gaussian process regression (GPR) and decision tree (DT). We optimized and evaluated the hyper-parameters of them using standard metrics. Boosted DT has an MAE error rate, an R2-score, and an MAPE of 6.806E-05, 0.980, and 4.511E-01, respectively. Also, boosted GPR has an R2-score of 0.998 and its MAPE error is 3.929E-02, and with MAE it has an error rate of 5.024E-06. So, boosted GPR was chosen as the best model, and the best values were: (T = 3.38E + 02, P = 4.0E + 02, Solubility = 0.001241).
Topics: Anti-Inflammatory Agents, Non-Steroidal; Humans; Machine Learning; Oxaprozin; Propionates; Solubility
PubMed: 35908085
DOI: 10.1038/s41598-022-17440-4 -
Scientific Reports Jul 2022These days, many efforts have been made to increase and develop the solubility and bioavailability of novel therapeutic medicines. One of the most believable approaches...
These days, many efforts have been made to increase and develop the solubility and bioavailability of novel therapeutic medicines. One of the most believable approaches is the operation of supercritical carbon dioxide fluid (SC-CO). This operation has been used as a unique method in pharmacology due to the brilliant positive points such as colorless nature, cost-effectives, and environmentally friendly. This research project is aimed to mathematically calculate the solubility of Oxaprozin in SC-CO through artificial intelligence. Oxaprozin is a nonsteroidal anti-inflammatory drug which is useful in arthritis disease to improve swelling and pain. Oxaprozin is a type of BCS class II (Biopharmaceutical Classification) drug with low solubility and bioavailability. Here in order to optimize and improve the solubility of Oxaprozin, three ensemble decision tree-based models including random forest (RF), Extremely random trees (ET), and gradient boosting (GB) are considered. 32 data vectors are used for this modeling, moreover, temperature and pressure as inputs, and drug solubility as output. Using the MSE metric, ET, RF, and GB illustrated error rates of 6.29E-09, 9.71E-09, and 3.78E-11. Then, using the R-squared metric, they demonstrated results including 0.999, 0.984, and 0.999, respectively. GB is selected as the best fitted model with the optimal values including 33.15 (K) for the temperature, 380.4 (bar) for the pressure and 0.001242 (mole fraction) as optimized value for the solubility.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Artificial Intelligence; Carbon Dioxide; Oxaprozin; Propionates; Solubility
PubMed: 35907929
DOI: 10.1038/s41598-022-17350-5 -
Canadian Journal of Physiology and... Jun 2022The effect of oxaprozin (OXP) on an experimental model of seizures in rats was investigated in this study. Seizures in Wistar rats (200-250 g) were induced by...
The effect of oxaprozin (OXP) on an experimental model of seizures in rats was investigated in this study. Seizures in Wistar rats (200-250 g) were induced by pentylenetetrazole (PTZ, 60 mg/kg). The anticonvulsant effect of OXP (100, 200, and 400 mg/kg, intraperitoneally) was evaluated in a seizure model. After behavioral tests, the animals underwent deep anesthesia and were put down painlessly. Animal serum was isolated for antioxidant assays (nitric oxide (NO) and glutathione (GSH)). The animals' brains were also isolated to gauge the relative expression of genes in the oxidative stress pathway (sirtuin 1 (Sirt1) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α)). Intraperitoneal injection of OXP increased the mean latency of myoclonic jerks and generalized tonic-clonic seizure (GTCS) and decreased the number of myoclonic jerks and GTCS duration compared with the PTZ group. Biochemical tests showed that pretreatment with OXP was able to restore GSH serum levels and reverse the augmented NO serum levels caused by PTZ induction to the normal level. The quantitative polymerase chain reaction results also revealed that OXP counteracts the negative effects of PTZ by affecting the expression of the and genes. Overall, this study suggests the potential neuroprotective effects of the nonsteroidal, anti-inflammatory OXP drug in a model of neural impairment caused by seizures via the mechanism of inhibition of the oxidative stress pathway.
Topics: Animals; Anticonvulsants; Disease Models, Animal; Glutathione; Myoclonus; Oxaprozin; Oxidative Stress; Pentylenetetrazole; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Rats, Wistar; Seizures; Sirtuin 1
PubMed: 35395161
DOI: 10.1139/cjpp-2021-0757 -
International Journal of Pharmaceutics Apr 2022Abraham model solute descriptors have been determined for nisoldipine, nizatidine, loratadine, zonisamide, oxaprozin, rebamipide, domperidone, temozolomide,...
Abraham model solute descriptors have been determined for nisoldipine, nizatidine, loratadine, zonisamide, oxaprozin, rebamipide, domperidone, temozolomide, 'florfenicol', florfenicol A, dapsone, chrysin, benorilate, β-lapachone, and Ipriflavone based on published partition coefficients, molar solubilities and gas chromatographic retention indices. The calculated solute descriptors, combined with our previously published Abraham model correlations, are used to predict several important physicochemical and biological properties, such as air-water, air-blood, air-lung, air-fat, air-skin, water-lipid, water-membrane and water-skin partition coefficients, as well as permeation from water through skin.
Topics: Chromatography, Gas; Solubility; Water
PubMed: 35181462
DOI: 10.1016/j.ijpharm.2022.121597 -
Journal of Molecular Neuroscience : MN Apr 2022There is substantial evidence that anti-inflammatory agents and antioxidants have neuroprotective properties and may be useful in the treatment of neurodegenerative...
Nonsteroidal Anti-inflammatory Drug Oxaprozin is Beneficial Against Seizure-induced Memory Impairment in an Experimental Model of Seizures in Rats: Impact On Oxidative Stress and Nrf2/HO-1 Signaling Pathway.
There is substantial evidence that anti-inflammatory agents and antioxidants have neuroprotective properties and may be useful in the treatment of neurodegenerative disorders. In this regard, the effects of oxaprozin (OXP) (a nonsteroidal anti-inflammatory drug) on the experimental model of seizure and memory impairment caused by seizures in rats were investigated in the present study. Seizures in male Wistar rats (200-250 g, 8 weeks) were induced by pentylenetetrazol (PTZ, 60 mg/kg). The anticonvulsant effects of OXP (100, 200, and 400 mg/kg, administered intraperitoneally) were evaluated in the seizure model. The effect on memory was assessed using the passive avoidance (PA) test. After behavioral tests, the animals underwent deep anesthesia and were euthanized painlessly. Animal serum was isolated for antioxidant assays (MDA and GPx). The animals' brains (hippocampus) were also isolated to gauge the relative expression of genes in the oxidative stress pathway (Nrf2/HO-1). Intraperitoneal injection of OXP decreased the mean score on the Racine scale compared to the PTZ group. Moreover, in the PA test, OXP caused a significant increase in retention latency (RL) and total time spent in the light compartment (TLC) compared to the PTZ group. Biochemical tests showed that OXP was able to significantly increase GPx serum levels and significantly reduce MDA serum levels compared to the PTZ group. Quantitative polymerase chain reaction (qPCR) results also revealed that OXP counteracted the negative effects of PTZ by significantly increasing the expression of the Nrf2 and Hmox1 genes. Overall, this study suggests the potential neuroprotective effects of the nonsteroidal anti-inflammatory drug OXP in a model of memory impairment caused by seizures via inhibition of the oxidative stress pathway.
Topics: Animals; Male; Rats; Anticonvulsants; Antioxidants; Disease Models, Animal; Memory Disorders; Models, Theoretical; NF-E2-Related Factor 2; Oxaprozin; Oxidative Stress; Pentylenetetrazole; Rats, Wistar; Seizures; Signal Transduction
PubMed: 35084669
DOI: 10.1007/s12031-022-01967-2 -
Current Drug Delivery 2022Oxaprozin is labeled as a Class II drug in the biopharmaceutical classification system, and its poor solubility in the entire gastrointestinal tract may be the main...
BACKGROUND
Oxaprozin is labeled as a Class II drug in the biopharmaceutical classification system, and its poor solubility in the entire gastrointestinal tract may be the main reason for its insufficient oral absorption capacity.
OBJECTIVE
The purpose of this study was to develop an oxaprozin formulation to enhance its oral absorption.
METHODS
Oxaprozin-loaded microemulsions were prepared using the titration method and pseudoternary phase diagram. Characterization experiments were performed on microemulsion preparations, including pH, particle size, shape, zeta potential, and stability (thermodynamic, dilution, and differential scanning calorimetry). Then, the in vitro release of the microemulsion and in vivo pharmacokinetics in rats were evaluated.
RESULTS
Several microemulsion formulations were prepared. The optimal formulation was 15% oleoyl macrogolglycerides, 35% Tween 20/isopropanol (Km=2), and 50% distilled water. Its particle size met the requirements, and it had a spherical shape with a negatively charged surface. This microemulsion-loaded drug was applied to in vitro release and in vivo pharmacokinetic experiments at 7.47 mg/mL. In vitro release of the oxaprozin-loaded microemulsion best fit the firstorder model, while the microemulsion preparation had a certain sustained-release effect. In vivo pharmacokinetic experiments indicated that the microemulsion formulation significantly delayed the peak time of the blood concentration and simultaneously prolonged the half-life of drug elimination.
CONCLUSION
The obtained data revealed satisfactory results for this novel microemulsion of oxaprozin, which is very meaningful for clinical trials.
Topics: Administration, Oral; Animals; Emulsions; Oxaprozin; Particle Size; Rats; Solubility
PubMed: 34521326
DOI: 10.2174/1567201818666210914092745 -
Biomedicines Jun 2021SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase...
Proof-of-Concept for the Analgesic Effect and Thermoregulatory Safety of Orally Administered Multi-Target Compound SZV 1287 in Mice: A Novel Drug Candidate for Neuropathic Pain.
SZV 1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime) is a novel multi-target candidate under preclinical development for neuropathic pain. It inhibits amine oxidase copper containing 3, transient receptor potential ankyrin 1 and vanilloid 1 (TRPV1) receptors. Mainly under acidic conditions, it is transformed to the cyclooxygenase inhibitor oxaprozin, which is ineffective for neuropathy. Therefore, an enterosolvent capsule is suggested for oral formulation, which we investigated for nociception, basic kinetics, and thermoregulatory safety in mice. The antihyperalgesic effect of SZV 1287 (10, 20, 50, and 200 mg/kg, p.o.) was determined in partial sciatic nerve ligation-induced traumatic neuropathy by aesthesiometry, brain and plasma concentrations by HPLC, and deep body temperature by thermometry. Its effect on proton-induced TRPV1 activation involved in thermoregulation was assessed by microfluorimetry in cultured trigeminal neurons. The three higher SZV 1287 doses significantly, but not dose-dependently, reduced neuropathic hyperalgesia by 50% of its maximal effect. It was quickly absorbed; plasma concentration was stable for 2 h, and it entered into the brain. Although SZV 1287 significantly decreased the proton-induced TRPV1-mediated calcium-influx potentially leading to hyperthermia, it did not alter deep body temperature. Oral SZV 1287 inhibited neuropathic hyperalgesia and, despite TRPV1 antagonistic action and brain penetration, it did not influence thermoregulation, which makes it a promising analgesic candidate.
PubMed: 34209525
DOI: 10.3390/biomedicines9070749 -
Molecules (Basel, Switzerland) May 2021The synthesis of novel triphenyltin(IV) compounds, PhSnL ( = 1-3), with oxaprozin (3-(4,5-diphenyloxazol-2-yl)propanoic acid), , and the new propanoic acid derivatives...
The synthesis of novel triphenyltin(IV) compounds, PhSnL ( = 1-3), with oxaprozin (3-(4,5-diphenyloxazol-2-yl)propanoic acid), , and the new propanoic acid derivatives 3-(4,5-bis(4-methoxylphenyl)oxazol-2-yl)propanoic acid, , and 3-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)propanoic acid, , has been performed. The ligands represent commercial drugs or their derivatives and the tin complexes have been characterized by standard analytical methods. The in vitro antiproliferative activity of both ligands and organotin(IV) compounds has been evaluated on the following tumour cell lines: human prostate cancer (PC-3), human colorectal adenocarcinoma (HT-29), breast cancer (MCF-7), and hepatocellular cancer (HepG2), as well as on normal mouse embryonic fibroblast cells (NIH3T3) with the aid of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-12 diphenyltetrazolium bromide) and CV (crystal violet) assays. Contrary to the inactive ligand precursors, all organotin(IV) carboxylates showed very good activity with IC values ranging from 0.100 to 0.758 µM. According to the CV assay (IC = 0.218 ± 0.025 µM), complex demonstrated the highest cytotoxicity against the caspase 3 deficient MCF-7 cell line. Inductively coupled plasma mass spectrometry (ICP-MS) analysis indicated a two-fold lower concentration of tin in MCF-7 cells in comparison to platinum. To investigate the mechanism of action of the compound on MCF-7 cells, morphological, autophagy and cell cycle analysis, as well as the activation of caspase and ROS/RNS and NO production, has been performed. Results suggest that induces caspase-independent apoptosis in MCF-7 cells.
Topics: Animals; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Gentian Violet; HT29 Cells; HeLa Cells; Humans; In Vitro Techniques; Inhibitory Concentration 50; Ligands; MCF-7 Cells; Mass Spectrometry; Metals; Mice; NIH 3T3 Cells; Neoplasms; Organotin Compounds; Reactive Nitrogen Species; Reactive Oxygen Species
PubMed: 34071809
DOI: 10.3390/molecules26113199 -
Journal of Medicinal Chemistry Apr 2021The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear...
The retinoid X receptors (RXR) are ligand-activated transcription factors involved in multiple regulatory networks as universal heterodimer partners for nuclear receptors. Despite their high therapeutic potential in many pathologies, targeting of RXR has only been exploited in cancer treatment as the currently available RXR agonists suffer from exceptional lipophilicity, poor pharmacokinetics (PK), and adverse effects. Aiming to overcome the limitations and to provide improved RXR ligands, we developed a new potent RXR ligand chemotype based on the nonsteroidal anti-inflammatory drug oxaprozin. Systematic structure-activity relationship analysis enabled structural optimization toward low nanomolar potency similar to the well-established rexinoids. Cocrystal structures of the most active derivatives demonstrated orthosteric binding, and profiling revealed superior PK properties compared to current RXR agonists. The optimized compounds were highly selective for RXR activation and induced RXR-regulated gene expression in native cellular and settings suggesting them as excellent chemical tools to further explore the therapeutic potential of RXR.
Topics: Animals; Binding Sites; Cell Survival; Crystallography, X-Ray; Half-Life; Humans; Ligands; Mice; Microsomes; Molecular Dynamics Simulation; Oxaprozin; Protein Isoforms; Pyrazoles; Rats; Retinoid X Receptors; Structure-Activity Relationship
PubMed: 33793232
DOI: 10.1021/acs.jmedchem.1c00235 -
Romanian Journal of Morphology and... 2020This paper reports the synthesis, analgesic activity, acute toxicity and histopathological (HP) assessment of four new compounds from oxazol-5(4H)-ones class that...
This paper reports the synthesis, analgesic activity, acute toxicity and histopathological (HP) assessment of four new compounds from oxazol-5(4H)-ones class that contain in their molecule a diarylsulfone moiety. The new 2-(4-(4-bromophenylsulfonyl)phenyl)-4-arylidene-oxazol-5(4H)-ones were obtained by reaction of 2-(4-(4-bromophenyl-sulfonyl)benzamido)acetic acid intermediate with aromatic aldehydes (benzaldehyde, 4-methoxy, 4-nitro or 4-bromobenzaldehyde), in acetic anhydride and in the presence of anhydrous sodium acetate. The new compounds have been characterized by spectral techniques, such as: Fourier-transform infrared spectroscopy (FT-IR), mass spectrometry (MS), proton nuclear magnetic resonance (1H-NMR) and by elemental analysis. The acute toxicity of the new oxazol-5(4H)-ones in mice was assessed through "acute toxic class" method, according to Organization for Economic Co-operation and Development (OECD) Guidelines. The HP assessment of some preserved organs collected from mice has been performed. The analgesic activity of all new synthesized compounds was carried out with two pharmacological tests: the writhing test and the hot plate test. In order to predict the binding affinities of the synthesized oxazol-5(4H)-ones derivatives against molecular targets involved in pain and inflammation, molecular docking simulations were performed. The results of the writhing test indicated that the most active compound was the oxazolone that contains in the molecule a methoxy group. The acute oral toxicity study revealed no lethal effect of new compounds. The HP assessment of the preserved organs collected from mice did not indicate any cytohistopathological aspects that can be linked to any inflammatory, neoplastic or cytotoxic process, demonstrating the low toxicity of new compounds.
Topics: Analgesics; Animals; Female; Humans; Mice; Oxaprozin
PubMed: 33544801
DOI: 10.47162/RJME.61.2.19