Propellant Free Pressurized Spray System of Etodolac to Manage Acute Pain Conditions: In Vitro and In Vivo Evaluation.

This study aimed to develop a propellant-free topical spray formulation of Etodolac (BCS-II), a potent NSAID, which could be beneficial in the medical field for the effective treatment of pain and inflammation conditions. The developed novel propellant-free spray formulation is user-friendly, cost-effective, propellant-free, eco-friendly, enhances the penetration of Etodolac through the skin, and has a quick onset of action. Various formulations were developed by adjusting the concentrations of different components, including lecithin, buffering agents, film-forming agents, plasticizers, and permeation enhancers. The prepared propellant-free spray formulations were then extensively characterized and evaluated through various in vitro, ex vivo, and in vivo parameters. The optimized formulation exhibits an average shot weight of 0.24 ± 0.30 ml and an average drug content or content uniformity of 87.3 ± 1.01% per spray. Additionally, the optimized formulation exhibits an evaporation time of 3 ± 0.24 min. The skin permeation study demonstrated that the permeability coefficients of the optimized spray formulation were 21.42 cm/h for rat skin, 13.64 cm/h for mice skin, and 18.97 cm/h for the Strat-M membrane. When assessing its potential for drug deposition using rat skin, mice skin, and the Strat-M membrane, the enhancement ratios for the optimized formulation were 1.88, 2.46, and 1.92, respectively against pure drug solution. The findings from our study suggest that the propellant-free Etodolac spray is a reliable and safe topical formulation. It demonstrates enhanced skin deposition, and improved effectiveness, and is free from any skin irritation concerns.

Perioperative escape from dormancy of spontaneous micro-metastases: A role for malignant secretion of IL-6, IL-8, and VEGF, through adrenergic and prostaglandin signaling.

We recently showed that a minimally-invasive removal of MDA-MB-231HM primary tumors (PTs) and elimination of their secreted factors (including IL-6, IL-8, VEGF, EGF, PDGF-aa, MIF, SerpinE1, and M-CSF), caused regression of spontaneous micro-metastases into a non-growing dormant state. To explore the underlying mechanisms and potential clinical ramifications of this phenomenon, we herein used the MDA-MB-231HM human breast cancer cell-line, in-vitro, and in vivo following orthotopic implantation in immune-deficient BALB/C nu/nu mice. Employing bioluminescence imaging, we found that adding laparotomy to minimally-invasive removal of the PT caused an outbreak of micro-metastases. However, perioperative ß-adrenergic and COX-2 inhibition, using propranolol + etodolac, maintained metastatic dormancy following laparotomy. In-vitro, ß-adrenergic agonists (epinephrine or metaproterenol) and prostaglandin-E2 markedly increased MDA-MB-231HM secretion of the pro-metastatic factors IL-6, IL-8, and VEGF, whereas cortisol reduced their secretion, effects that were maintained even 12 h after the washout of these agonists. In-vivo, laparotomy elevated IL-6 and IL-8 levels in both plasma and ex-vivo PT spontaneous secretion, whereas perioperative propranolol + etodolac administration blocked these effects. Similar trends were evident for EGF and MIF. Promoter-based bioinformatics analyses of excised PT transcriptomes implicated elevated NF-kB activity and reduced IRF1 activity in the gene regulatory effects of laparotomy, and these effects were inhibited by pre-surgical propranolol + etodolac. Taken together, our findings suggest a novel mechanism of post-operative metastatic outbreak, where surgery-induced adrenergic and prostanoid signaling increase the secretion of pro-metastatic factors, including IL-6, IL-8, and VEGF, from PT and possibly residual malignant tissue, and thereby prevent residual disease from entering dormancy.

Sensitive and selective LC-MS/MS for the determination of tolperisone and etodolac in human plasma and application to a pharmacokinetic study.

Tolperisone and etodolac were proven to have synergistic effect for patients of acute low back pain associated with musculoskeletal spasm. In this work, a specific, highly sensitive and reproducible analytical method was developed and validated for the simultaneous determination of tolperisone and etodolac in human plasma using liquid chromatography-tandem mass spectrometric technique. Liquid-liquid extraction was optimized for sample preparation. Zorbax C8 column (3.5 µm, 50 × 4.6 mm) was used, carrying a mobile phase mixture of 10.0 mM ammonium formate:acetonitrile (40:60, v/v) pH 3.8, running in an isocratic mode. Chlorzoxazone acted as an internal standard. Sample volume of injection was 5.0 µL, and analysis was achieved within 2.5 min. Detection and quantitation were performed by electrospray ionization mass spectrometry using the multiple-reaction monitoring mode. The proposed method could determine the analytes in the range of concentration 0.5-200.0 ng mL-1 for tolperisone and 0.05-20.0 µg mL-1 for etodolac. Findings of inter- and intraday precisions were ≤12.3% with accuracy of ±5.0%. Pharmacokinetics study for the two drugs after oral administration of healthy human volunteers was achieved with the aid of application of the developed study.

Nanostructured Lipid Carriers (NLC)-Based Gel Formulations as Etodolac Delivery: From Gel Preparation to Permeation Study.

Topical administration of drug is an attractive alternative to the oral administration as it provides a reduction in adverse reactions and an enhancement of therapeutic effects. The use of lipid carriers in hydrogel structures makes it possible to introduce lipophilic substances in a dissolved form. In this study, an NSAID from the BCS class II, etodolac (ETD), was used. The nanostructured lipid carriers (NLC) obtained with ETD were incorporated into semi-solid forms (gels). Hydrogels with the suspended drug and oleogel were also prepared for comparison purposes. The obtained gels were tested in terms of pH, viscosity, rheological, mechanical, and bioadhesive properties. The release and permeation through membranes were also studied. All tested formulations were characterized by a pH below 7, which ensured the physiological state of the skin. The viscosities of all gels decreased with increasing shear rate, indicating non-Newtonian behavior. The fastest ETD release was observed for NLC with a Carbopol base (formulation F1); a similar result was noticed in the permeation test. The developed gel formulations containing ETD-NLC dispersion and Carbopol or Poloxamer as gelling agents were stable and possessed beneficial pharmaceutical properties.

Transfersome Hydrogel Containing 5-Fluorouracil and Etodolac Combination for Synergistic Oral Cancer Treatment.

Oral cancer is one of the most common malignancies with an increased rate of incidence. 5-Fluorouracil (5FU) is an effective chemotherapeutic indicated for oral cancer treatment. Etodolac (Et), a cyclooxygenase-2 inhibitor, can be used as an adjuvant agent to sensitize cancer cells to chemotherapy. The aim of this work was to prepare and characterize 5FU and Et dual drug-loaded transfersomes to treat oral cancer. Transfersomes were prepared by thin-film hydration method and characterized for the average particle size and zeta-potential using dynamic light scattering and scanning electron microscopy techniques. The prepared transfersomes were further characterized for their drug loading, entrapment efficiencies using amicon centrifuge tubes and drug release behavior using cellulose membrane. The synergistic activity of dual drug-loaded transfersomes was studied in FaDu oral cancer cells. Results showed that the average particle size, polydispersity index, and zeta potential were 91±6.4 nm, 0.28±0.03, and (-)46.9±9.5 mV, respectively, for 5FU- and Et (1:1)-loaded transfersomes. The highest encapsulation efficiency achieved was 36.9±3.8% and 79.8±6.4% for 5FU and Et (1:1), respectively. Growth inhibition studies in FaDu cells using different concentrations of 5FU and Et showed a combination index of 0.36, indicating a synergistic effect. The FaDu cell uptake of drug-loaded transfersomes was significantly (p<0.05) greater than that of free drugs. The transfersome hydrogel made of HPMC (2% w/w) showed similar flux, lag time, and permeation coefficient as that of drug-loaded transfersomes across excised porcine buccal tissue. In conclusion, 5FU and Et transfersome hydrogel can be developed for localized delivery to treat oral cancer.

Effectiveness of transcutaneous electrical nerve stimulation as an adjunct to selected physical therapy exercise program on male patients with pudendal neuralgia: A randomized controlled trial.

OBJECTIVE: To assess the effectiveness of Transcutaneous Electrical Nerve Stimulation (TENS) combined with selected physical therapy exercise program on male patients with pudendal neuralgia. DESIGN: A double-blinded randomized controlled study. SETTING: Out-patient setting. PARTICIPANTS: Fifty-two male participants with pudendal neuralgia (30-50 years) were allocated randomly into two groups; study and control. The same physical therapy exercises were applied to all participants, plus the same prescribed analgesic medication (Etodolac). Participants in the study group received additional TENS and sham TENS were given to those in control group. INTERVENTION: Intervention lasted for 12 weeks, three sessions per week (60 minutes/session). OUTCOME MEASURES: Numerical pain rating scale and daily Etodolac intake dose were measured before and after intervention. RESULTS: Statistically significant differences were detected in numerical pain rating scale and daily Etodolac intake in favor of the study group (P < 0.05). After 12 weeks of intervention, the mean ± SD for numerical pain rating scale and daily Etodolac intake were 4.25 ± 1.9 and 259.25 ± 84.4 mg, in the study group, and 6.22 ± 2.22 and 355.55 ± 93.36 mg in the control group, respectively. The mean difference (95% CI) for numerical pain rating scale and daily Etodolac intake was -1.97 (-3.09: -0.83) and -96.3 (-144.9: -47.69), between groups post treatment, respectively. CONCLUSION: Adding TENS to physical therapy exercise program is more effective than physical therapy program alone in improving pain in male patients with pudendal neuralgia as measured by numerical pain rating scale and daily analgesic intake dose.

Etodolac nanosuspension based gel for enhanced dermal delivery: in vitro and in vivo evaluation.

AIM: The objective of this study was to develop dermal nanosuspension (NS) based gel formulation of etodolac (ETD). METHODS: Etodolac nanosuspension (ETD-NS) was prepared by wet milling method and dispersed in hydroxypropyl methylcellulose (NS-HPMC) or hydroxyethyl cellulose (NS-HEC) gels. Rheologic and mechanical properties were investigated. In vitro and ex vivo permeability studies were performed. Topical anti-inflammatory and analgesic activity were evaluated in regard to carrageenan-induced inflammatory paw oedema and radiant heat tail-flick method, respectively. RESULTS: The ETD-NS with approximately 190 nm particle size (PS), 0.16 polydispersity index (PDI), and -15 mV zeta potential (ZP) values were obtained. The work of bioadhesion values of NS-HEC and NS-HPMC gels were 0.229 mJ/cm2 for both gels. Dermal permeation of ETD from NS-HEC gel (7.18%) was found significantly higher than the NS-HPMC gel (4.56%). Enhanced anti-inflammatory and analgesic activity of NS-HEC gels were observed in comparison with micronised ETD. CONCLUSIONS: ETD-NS based gel formulation is promising for topical delivery of ETD.

Application of Design of Experiments® Approach-Driven Artificial Intelligence and Machine Learning for Systematic Optimization of Reverse Phase High Performance Liquid Chromatography Method to Analyze Simultaneously Two Drugs (Cyclosporin A and Etodolac) in Solution, Human Plasma, Nanocapsules, and Emulsions.

The objectives of current investigation are (1) to find out wavelength of maximum absorbance (λmax) for combined cyclosporin A and etodolac solution followed by selection of mobile phase suitable for the RP-HPLC method, (2) to define analytical target profile and critical analytical attributes (CAAs) for the analytical quality by design, (3) to screen critical method parameters with the help of full factorial design followed by optimization with face-centered central composite design (CCD) approach-driven artificial neural network (ANN)-linked with the Levenberg-Marquardt (LM) algorithm for finding the RP-HPLC conditions, (4) to perform validation of analytical procedures (trueness, linearity, precision, robustness, specificity and sensitivity) using combined drug solution, and (5) to determine drug entrapment efficiency value in dual drug-loaded nanocapsules/emulsions, percentage recovery value in human plasma spiked with two drugs and solution state stability analysis at different stress conditions for substantiating the double-stage systematically optimized RP-HPLC method conditions. Through isobestic point and scouting step, 205 nm and ACN:H2O mixture (74:26) were selected respectively as the λmax and mobile phase. The ANN topology (3:10:4) indicating the input, hidden and output layers were generated by taking the 20 trials produced from the face-centered CCD model. The ANN-linked LM model produced minimal differences between predicted and observed values of output parameters (or CAAs), low mean squared error and higher correlation coefficient values in comparison to the respective values produced by face-centered CCD model. The optimized RP-HPLC method could be applied to analyze two drugs concurrently in different formulations, human plasma and solution state stability checking.

The association between nonsteroidal anti-inflammatory drugs and skin cancer: Different responses in American and European populations.

OBJECTIVE: To conduct a comprehensive systematic meta-analysis investigating the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and their subtypes with skin cancer (SC) and its subclasses (basal cell carcinoma BCC; squamous cell carcinoma SCC; melanoma; nonmelanoma skin cancer NMSC) in general, American and European populations. METHODS: PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure and ClinicalTrials.gov were searched up to 24 February 2019. Pooled effect sizes and 95% confidence intervals were used to estimate associations. RESULTS: Results based on 26 original studies including 223,619 cases and 1,398,507 controls showed both NSAIDs and nonselective Cyclooxygenase (COX) inhibitors to be statistically significantly associated with a reduced risk of SC, BCC, SCC and NMSC but not with melanoma. Conversely, no association was observed between selective Cyclooxygenase 2 (COX-2) inhibitors and SC or its subclasses. Further subgroup analysis showed that the results analyzed for American populations were almost the same as those for the general population. For European populations, neither NSAIDs nor its subtypes correlated significantly with susceptibility to SC or its subclasses. CONCLUSIONS: The use of NSAIDs might reduce the risk of SC, but many factors including study population, drug subtype, and disease subclass affect the significance of the association.

Investigation of Formulation and Process Parameters of Wet Media Milling to Develop Etodolac Nanosuspensions.

PURPOSE: Etodolac (ETD) is one of the non-steroidal anti-inflammatory drugs which has low aqueous solubility issues. The objective of this study was to develop ETD nanosuspensions to improve its poor aqueous solubility properties while investigating formulation and process parameters of wet media milling method via design of experiment (DoE) approach. METHODS: The critical formulation parameters (CFP) were selected as ETD amount, stabilizer type and ratio as well as critical process parameters (CPP) which were bead size, milling time and milling speed. The two-factorial-23 and The Box-Benkhen Designs were generated to evaluate CFP and CPP, respectively. Particle size (PS), polydispersity index (PDI) and zeta potential (ZP) were analyzed as dependent variables. Characterization, physical stability and solubility studies were performed. RESULTS: Optimum nanosuspensions stabilized by PVP K30 and Poloxamer 188 showed 188.5 ± 1.6 and 279.3 ± 6.1 nm of PS, 0.161 ± 0.049 and 0.345 ± 0.007 PDI, 14.8 ± 0.3 and 16.5 ± 0.4 mV of ZP values, respectively. The thermal properties of ETD did not change after milling and lyophilization process regarding to DSC analysis. Also, the crystalline state of ETD was preserved. The morphology of particle was smooth and spherical on SEM. The dry-nanosuspensions stayed physically stable for six months at room temperature. The solubility of nanosuspensions increased up to 13.0-fold in comparison with micronized ETD. CONCLUSIONS: In conclusion, it is found that the poor solubility issue of ETD can be solved by nanosuspension. DoE approach provided benefits such as reducing number of experiments, saving time and improving final product quality by using wet media milling.

Liquid chromatographic methods for separation, determination, and bioassay of enantiomers of etodolac: A review.

The control of enantiomeric purity and determination of individual enantiomeric drug molecules remains the subject of importance for clinical, analytical, and regulatory purposes and to facilitate an accurate evaluation of the risks posed by them to human health. A large number of pharmaceuticals are marketed and administered as racemates. Etodolac is among such nonsteroidal anti-inflammatory drugs. Overall literature reports on its enantioseparation are scanty. Liquid chromatography (LC) methods of enantioseparation of (±)-etodolac, including certain unconventional ones, are well covered and discussed in this paper. Methods of direct approach without using chiral columns or chiral thin-layer chromatography plate and of indirect approach using certain chiral derivatizing agents such as (S)-naproxen and (S)-levofloxacin are described. Most interesting aspects include establishment of structure and molecular asymmetry of chemically different types of diastereomeric derivatives using liquid chromatography with mass spectrometry (LC-MS), 1 H NMR spectroscopy and by drawing conformations in three dimensional views by using certain software. The methods provide chirality recognition even in the absence of pure enantiomers. Besides, recovery of pure enantiomers by detagging or via solubility difference of chiral inducing reagent and the analyte, without racemization at any stage, has been achieved. The limits of detection and quantification are much lower than the industry benchmarks.

Pharmacokinetic modeling and simulation of etodolac following single oral administration in dogs.

Etodolac is a nonsteroidal anti-inflammatory drug with selective cyclooxygenase-2 inhibition to treat pain and inflammation associated with osteoarthritis in humans and dogs. The aim of the study was to investigate the pharmacokinetics of etodolac following single oral administration of 200 mg to 10 healthy beagle dogs. The plasma concentrations of etodolac were detected using liquid chromatography-tandem mass spectrometry. Pharmacokinetic analysis was conducted using the noncompartmental method and modeling approaches. Etodolac was rapidly absorbed (Tmax = 0.85 h, Ka = 1.49 h-1) and slowly eliminated (T1/2 = 39.55 h) following oral administration to the dogs. A two-compartment pharmacokinetic model with first-order absorption and elimination rate constants was successfully explained for the pharmacokinetic aspects of etodolac in dogs. From a Monte Carlo simulation (1000 repetitions), the accumulation index and AUCτ at steady state were predicted as 1.60 [90% confidence intervals (CI), 1.24-2.81] and 408.18 ng·hr/mL [90% CI, 271.26-590.58 ng·hr/mL], respectively. This study will help to enact a more accurate optimal dosing regimen of etodolac in dogs with osteoarthritis, and may be useful in developing a novel formulation of etodolac for human in the future.

Liquid chromatographic enantioseparation of (RS)-etodolac using (S)-levofloxacin and determination of absolute configuration of the diastereomeric derivatives.

(RS)-Etodolac was isolated from commercial tablets and was purified and characterized to be used as racemic standard. A pair of diastereomeric derivatives was synthesized using (S)-levofloxacin as a chiral derivatizing reagent. The derivatization reaction was carried out under conditions of stirring at room temperature (30°C for 1.5 h) as well as under microwave irradiation; the derivatives obtained by the two methods were compared. Reaction conditions for derivatization were optimized with respect to mole ratio of chiral derivatizing reagent and (RS)-etodolac. No racemization was observed throughout the study. Separation of diastereomeric derivatives was successful using C18 column and a binary mixture of methanol and triethyl ammonium phosphate buffer of pH 4.5 (80:20, v/v) as mobile phase at a flow rate of 1 mL min-1 and UV detection at 223 nm. An efficient approach for recognizing chirality and determining the absolute configuration of the diastereomeric derivatives of (RS)-etodolac is described, which in turn is a measure of the enantiomeric purity of (RS)-etodolac since the diastereomeric derivatives were separated and isolated using preparative thin-layer chromatography.

Perioperative inhibition of ß-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 expression, serum cytokine levels, and PBMCs transcriptome.

Catecholamines and prostaglandins are secreted abundantly during the perioperative period in response to stress and surgery, and were shown by translational studies to promote tumor metastasis. Here, in a phase-II biomarker clinical trial in breast cancer patients (n = 38), we tested the combined perioperative use of the ß-blocker, propranolol, and the COX2-inhibitor, etodolac, scheduled for 11 consecutive perioperative days, starting 5 days before surgery. Blood samples were taken before treatment (T1), on the mornings before and after surgery (T2&T3), and after treatment cessation (T4). Drugs were well tolerated. Results based on a-priori hypotheses indicated that already before surgery (T2), serum levels of pro-inflammatory IL-6, CRP, and IFNγ, and anti-inflammatory, cortisol and IL-10, increased. At T2 and/or T3, drug treatment reduced serum levels of the above pro-inflammatory cytokines and of TRAIL, as well as activity of multiple inflammation-related transcription factors (including NFκB, STAT3, ISRE), but not serum levels of cortisol, IL-10, IL-18, IL-8, VEGF and TNFα. In the excised tumor, treatment reduced the expression of the proliferation marker Ki-67, and positively affected its transcription factors SP1 and AhR. Exploratory analyses of transcriptome modulation in PBMCs revealed treatment-induced improvement at T2/T3 in several transcription factors that in primary tumors indicate poor prognosis (CUX1, THRa, EVI1, RORa, PBX1, and T3R), angiogenesis (YY1), EMT (GATA1 and deltaEF1/ZEB1), proliferation (GATA2), and glucocorticoids response (GRE), while increasing the activity of the oncogenes c-MYB and N-MYC. Overall, the drug treatment may benefit breast cancer patients through reducing systemic inflammation and pro-metastatic/pro-growth biomarkers in the excised tumor and PBMCs.

Synthesis, anticancer activity, and molecular modeling of etodolac-thioether derivatives as potent methionine aminopeptidase (type II) inhibitors.

A series of (R,S)-1-{[5-(substituted)sulfanyl-4-substituted-4H-1,2,4-triazole-3-yl]methyl}-1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indoles (5a-v) were designed and synthesized using a five-step synthetic protocol that involves substituted benzyl chlorides and (R,S)-5-[(1,8-diethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-yl)methyl]-4-substituted-2,4-dihydro-3H-1,2,4-triazole-3-thiones in the final step. The synthesized derivatives were evaluated for cytotoxicity and anticancer activity in vitro using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) colorimetric method against VERO, HEPG2 (human hepatocellular liver carcinoma), SKOV3 (ovarian carcinoma), MCF7 (human breast adenocarcinoma), PC3 and DU145 (prostate carcinoma) cells at 10-5 M (10 µM) for 24 h. Compounds 5d and 5h showed the best biological potency against the SKOV3 cancer cell line (IC50 = 7.22 and 5.10 µM, respectively) and did not display cytotoxicity toward VERO cells compared to etodolac. Compounds 5k, 5s, and 5v showed the most potent biological activity against the PC3 cancer cell line (IC50 = 8.18, 3.10, and 4.00 µM, respectively) and did not display cytotoxicity. Moreover, these compounds were evaluated for caspase-3, -9, and -8 protein expression and activation in the apoptosis pathway for 6, 12, and 24 h, which play a key role in the treatment of cancer. In this study, we also investigated the apoptotic mechanism and molecular modeling of compounds 5k and 5v on the methionine aminopeptidase (type II) enzyme active site in order to get insights into the binding mode and energy.

Performance and microbial shift during acidification of a real pharmaceutical wastewater by using an anaerobic sequencing batch reactor (AnSBR).

In this study, a lab-scale anaerobic sequencing batch reactor (AnSBR) was used for the acidification of a pharmaceutical wastewater sourced from etodolac chemical synthesis tanks. The effects of the organic loading rate (OLR), and etodolac and sulfate concentrations on the acidification rate and microbial community in AnSBR were investigated at 35 °C with a hydraulic retention time (HRT) of 37 h, a pH of 5, and OLRs up to 5.2 kgCOD/m3·day. The AnSBR accomplished a 60% acidification ratio and 50-60% etodolac removal at OLRs up to 2.6 kgCOD/m3·day. However, at OLR = 3.9 kgCOD/m3·day, acidification was not achieved due to sulfite inhibition; pre-ozonation was applied to overcome this sulfite inhibition. Although etodolac and COD removals were improved, the wastewater was not successfully acidified. Real-time polymerase chain reaction (Q-PCR) and fluorescent in situ hybridization (FISH) analyses revealed that acidification was inhibited by the dominance of sulfate reducing bacteria (SRB) over acidification bacteria in the AnSBR. However, increasing the OLR to 5.2 kgCOD/m3·day led to toxicity stress in the SRB due to increased sulfite concentrations. Sulfate load fundamentally affected acidification process and microbial community composition. The presence of etodolac with concentration up to 56 mg/L did not have a significant effect on VFA production and the microbial community.

Preparation, Characterization and In Vitro / In Vivo Evaluation of Oral Time-Controlled Release Etodolac Pellets.

The objective of this study was to prepare time-controlled release etodolac pellets to facilitate drug administration according to the body's biological rhythm, optimize the drug's desired effects, and minimize adverse effects. The preparation consisted of three laminal layers from center to outside: the core, the swelling layer, and the insoluble polymer membrane. Factors influenced the core and the coating films were investigated in this study. The core pellets formulated with etodolac, lactose, and sodium carboxymethyl starch (CMS-Na) were prepared by extrusion-spheronization and then coated by a fluidized bed coater. Croscarmellose sodium (CC-Na) was selected as the swelling agent, and ethyl cellulose (EC) as the controlled release layer. The prepared pellets were characterized by scanning electron microscopy and evaluated by a dissolution test and a pharmacokinetic study. Compared with commercial available capsules, pharmacokinetics studies in beagle dogs indicated that the prepared pellets release the drug within a short period of time, immediately after a predetermined lag time. A good correlation between in vitro dissolution and in vivo absorption of the pellets was exhibited in the analysis.

Inclusion Complexation of Etodolac with Hydroxypropyl-beta-cyclodextrin and Auxiliary Agents: Formulation Characterization and Molecular Modeling Studies.

The present investigation was aimed to prepare inclusion complexes of a therapeutically important nonsteroidal anti-inflammatory drug, etodolac (ETD) with hydroxypropyl-beta-cyclodextrin (HP-ß-CD) and to study the effect of l-arginine (l-Arg) as an auxiliary agent on the complexation efficiency of HP-ß-CD to improve aqueous solubility and the dissolution property of ETD. The binary and ternary complexes were prepared by physical mixing, coevaporation, and spray drying methods. The complexes were characterized using differential scanning colorimetry (DSC), Fourier transform-infrared spectroscopy (FT-IR), and powder X-ray diffraction (PXRD) studies. The mechanism of inclusion interaction of guest and host was established through 1H NMR, molecular docking, and molecular dynamics studies. On the basis of preliminary screening studies, l-Arg was found to be the most efficient auxiliary agent for the present research problem. The change in crystallinity of ETD was evident from DSC and PXRD studies which indicated the formation of new solid forms. A remarkable increase in apparent stability constant (Kc) and complexation efficiency (CE) of HP-ß-CD was observed in the presence of l-Arg in ternary complexes with improvement in solubility and dissolution of ETD than binary complexes. However, inclusion complexes of ETD obtained by computational studies is in good correlation with the results obtained through experimental methods. More stable complex formation with l-Arg was confirmed by molecular simulation studies too. Thus, the present study led to the conclusion that the ternary complex of ETD-HP-ß-CD-l-Arg could be an innovative approach to augment the solubility and dissolution behavior of ETD.

Chiral separation and modeling of baclofen, bupropion, and etodolac profens on amylose reversed phase chiral column.

Chiral resolution of baclofen, bupropion, and etodolac profens was obtained with amylose derivatized chiral reversed stationary phase (carbamate groups). The eluent used for bupropion and etodolac was MeOH-water (20:80, v/v) and for baclofen was water-methanol (95:5, v/v). The eluent run rates, finding wavelength and temperature, were 1.0 mL/min, 220 nm and 27 ± 1 °C for all the eluents. The magnitude of the retardation factors for S- and R-enantiomers of baclofen, bupropion, and etodolac were 1.37, 2.62, 2.25, 3.25, 1.8, and 3.0. The magnitudes of separation and resolution factors were 1.90, 1.44, and 1.67 and 2.77, 2.35, and 2.04. Limits of detection and quantitation were 1.0-2.0 and 5.1-10.0 µg/mL. Chiral recognition mechanisms were recognized by simulation and high-performance liquid chromatography (HPLC) experiments. It was seen that hydrogen interactions, hydrophobic interactions, and π-π exchanges were the chief interactions for chiral recognition mechanisms. The described methods may be exploited for the chiral separation of baclofen, bupropion, and etodolac profens in any unknown sample.

Reducing liver metastases of colon cancer in the context of extensive and minor surgeries through ß-adrenoceptors blockade and COX2 inhibition.

Liver metastases are a major cause of colorectal cancer death, and the perioperative period is believed to critically affect the metastatic process. Here we tested whether blocking excess release of catecholamines and prostaglandins during surgical procedures of different extent can reduce experimental liver metastasis of the syngeneic CT26 colon cancer in female and male BALB/c mice. Animals were either treated with the beta-blocker, propranolol, the COX-2 inhibitor, etodolac, both drugs, or vehicle. The role of NK cells in controlling CT26 hepatic metastasis and in mediating the effect of the drugs was assessed by in vivo depletion or stimulation of NK cells, using anti-asialo GM1 or CpG-C, respectively. Surgical extent was manipulated by adding laparotomy to small incision, extending surgical duration, and enabling hypothermia. The results indicated that combined administration of propranolol and etodolac, but neither drug alone, significantly improved host resistance to metastasis. These beneficial effects occurred in both minor and extensive surgeries, in both sexes, and in two tumor inoculation approaches. NK cell-mediated anti-CT26 activity is involved in mediating the beneficial effects of the drugs. Specifically, CpG-C treatment, known to profoundly activate mice marginating-hepatic NK cytotoxicity, reduced CT26 hepatic metastases; and NK-depletion increased metastases and prevented the beneficial effects of the drugs. Overall, given prevalent perioperative psychological and physiological stress responses in patients, and ample prostaglandin release by colorectal tumors and injured tissue, propranolol and etodolac could be tested clinically in laparoscopic and open colorectal surgeries, attempting to reduce patients' metastatic disease.