Fabrication and Evaluation of Celecoxib Oral Oleogel to Reduce the Inflammation of Ulcerative Colitis.

Oleogel consists of hydrophobic solvent and an oleogelator. In this study, attempts were made to study the influence of Celecoxib solubility, concentration and dispersability on its release, absorption, and biological performance. Oleogels were prepared to study the formulation variables on its stability and release. Castor oil was selected as the oil and the oleogelator concentration was 4.5% w/w. F3 revealed the highest release and stability compared to other formulae. The percent permeated across the rat intestine showed a 7.5-fold increase over free Celecoxib, and its lifetime was found to be greater than 18 months. The efficacy of free Celecoxib and oleogel formulae to treat rats with ulcerative colitis was done via the induction of ulcerative colitis (UC) through administration of 5% dextran sodium sulphate (DSS). Celecoxib besides its formulae significantly reduced the release of Leucine rich 2 glycoprotein (LRG), Myeloperoxidase (MPO), Tumor necrosis factor-α (TNF-α), proinflammatory cytokine expression, High mobility group box 1 (HMGB1), Nuclear factor kappa B (NF-ΚB), Trefoil Factor 3 (TFF3), Metalloproteinase-3 (MMP3), and miRNA31. Moreover, F3 significantly increased the colonic cAMP in DSS treated rats and reduced the intestinal inflammation beside healing of mucosa and restitution of the epithelium of the gastrointestinal tract.

Effect of different oleogelators on lipolysis and curcuminoid bioaccessibility upon in vitro digestion of sunflower oil oleogels.

Sunflower oil enriched with curcuminoid compounds (CUs) was gelled by adding 5% (w/w) saturated monoglycerides (MG), rice bran waxes (RW) or a mixture of ß-sitosterol and γ-oryzanol (PS). The resulting oleogels differed for rheological properties and firmness due to the difference in gel network structure. PS oleogel was the firmest sample followed by RW and MG ones. Upon in vitro digestion, fatty acid release as a function of digestion time was greatly affected by oleogel structure: the extent of lipolysis decreased as oleogel strength increased (PS < RW < MG). On the other hand, the nature of the oleogelator affected CUs bioaccessibility, which was lower in oleogels containing crystalline particles (MG and RW). These findings appear interesting in the attempt to develop oleogels able to control lipid digestion as well as to deliver bioactive molecules in food systems.

Repositioning organohalogen drugs: a case study for identification of potent B-Raf V600E inhibitors via docking and bioassay.

Drug repositioning has been attracting increasingly attention for its advantages of reducing costs and risks. Statistics showed that around one quarter of the marketed drugs are organohalogens. However, no study has been reported, to the best of our knowledge, to aim at efficiently repositioning organohalogen drugs, which may be attributed to the lack of accurate halogen bonding scoring function. Here, we present a study to show that two organohalogen drugs were successfully repositioned as potent B-Raf V600E inhibitors via molecular docking with halogen bonding scoring function, namely D(3)DOCKxb developed in our lab, and bioassay. After virtual screening by D(3)DOCKxb against the database CMC (Comprehensive Medicinal Chemistry), 3 organohalogen drugs that were predicted to form strong halogen bonding with B-Raf V600E were purchased and tested with ELISA-based assay. In the end, 2 of them, rafoxanide and closantel, were identified as potent inhibitors with IC50 values of 0.07 µM and 1.90 µM, respectively, which are comparable to that of vemurafenib (IC50: 0.17 µM), a marketed drug targeting B-Raf V600E. Single point mutagenesis experiments confirmed the conformations predicted by D(3)DOCKxb. And comparison experiment revealed that halogen bonding scoring function is essential for repositioning those drugs with heavy halogen atoms in their molecular structures.

Bioavailability of organic phosphorus to Pseudokirchneriella subcapitata as affected by phosphorus starvation: an isotope dilution study.

Phosphorus (P) starved algae have a capacity to rapidly take up P when resupplied to P. This study was set-up to measure to what extent P starvation enhances the potential of algae to utilize organic P forms. The initial (<0.5 h) PO4 uptake rates of cells of Pseudokirchneriella subcapitata increased up to 18-fold with increasing starvation. Algae from different levels of P starvation were subsequently exposed to different model organic P forms and carrier-free (33)PO4. Uptake (1h) of P from organic P-increased up to 5-fold with increasing P starvation. The bioavailability of organic P, relative to PO4, was calculated from uptake of (31)P and (33)P isotopes assuming no isotopic exchange with organic P-forms. This relative bioavailability ranged from 0 to 57% and remained generally unaffected by the extent of P-starvation. This result was found for cells that were either or not treated by a wash method to remove extracellular phosphatases. Short-term P uptake rate sharply increases with decreasing internal P content of the algal cells but the bioavailability of organic P, relative to PO4, is not enhanced. Such finding suggests that P-starvation enhances PO4 uptake capacity and organic P hydrolysis capacity to about the same extent.

Simultaneous delivery of chemotherapeutic and thermal-optical agents to cancer cells by a polymeric (PLGA) nanocarrier: an in vitro study.

PURPOSE: To test the effectiveness of a dual-agent-loaded PLGA nanoparticulate drug delivery system containing doxorubicin (DOX) and indocyanine green (ICG) in a DOX-sensitive cell line and two resistant cell lines that have different resistance mechanisms. METHODS: The DOX-sensitive MES-SA uterine sarcoma cell line was used as a negative control. The two resistant cell lines were uterine sarcoma MES-SA/Dx5, which overexpresses the multidrug resistance exporter P-glycoprotein, and ovarian carcinoma SKOV-3, which is less sensitive to doxorubicin due to a p53 gene mutation. The cellular uptake, subcellular localization and cytotoxicity of the two agents when delivered via nanoparticles (NPs) were compared to their free-form administration. RESULTS: The cellular uptake and cytotoxicity of DOX delivered by NPs were comparable to the free form in MES-SA and SKOV-3, but much higher in MES-SA/Dx5, indicating the capability of the NPs to overcome P-glycoprotein resistance mechanisms. NP-encapsulated ICG showed slightly different subcellular localization, but similar fluorescence intensity when compared to free ICG, and retained the ability to generate heat for hyperthermia delivery. CONCLUSION: The dual-agent-loaded system allowed for the simultaneous delivery of hyperthermia and chemotherapy, and this combinational treatment greatly improved cytotoxicity in MES-SA/Dx5 cells and to a lesser extent in SKOV-3 cells.

ADME evaluation in drug discovery. 7. Prediction of oral absorption by correlation and classification.

A critically evaluated database of human intestinal absorption for 648 chemical compounds is reported in this study, among which 579 are believed to be transported by passive diffusion. The correlation analysis between the intestinal absorption and several important molecular properties demonstrated that no single molecular property could be used as a good discriminator to efficiently distinguish the poorly absorbed compounds from those that are well absorbed. The theoretical correlation models for a training set of 455 compounds were proposed by using the genetic function approximation technique. The best prediction model contains four molecular descriptors: topological polar surface area, the predicted distribution coefficient at pH = 6.5, the number of violations of the Lipinski's rule-of-five, and the square of the number of hydrogen-bond donors. The model was able to predict the fractional absorption with an r = 0.84 and a prediction error (absolute mean error) of 11.2% for the training set. Moreover, it achieves an r = 0.90 and a prediction error of 7.8% for a 98-compound test set. The recursive partitioning technique was applied to find the simple hierarchical rules to classify the compounds into poor (%FA < or = 30%) and good (%FA > 30%) intestinal absorption classes. The high quality of the classification model was validated by the satisfactory predictions on the training set (correctly identifying 95.9% of the compounds in the poor-absorption class and 96.1% of the compounds in the good-absorption class) and on the test set (correctly identifying 100% of the compounds in the poor-absorption class and 96.8% of the compounds in the good-absorption class). We expect that, in the future, the rules for the prediction of carrier-mediated transporting and first pass metabolism can be integrated into the current hierarchical rules, and the classification model may become more powerful in the prediction of intestinal absorption or even human bioavailability. The databases of human intestinal absorption reported here are available for download from the supporting Web site: http://modem.ucsd.edu/adme.

The clinical pharmacology of antiretrovirals in development.

Drugs in development for the management of HIV type 1 (HIV-1) infection include agents in existing classes and agents of novel classes. Of existing classes, new protease inhibitors, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors are in development. Novel therapeutic approaches include the development of chemokine receptor (CCR)5 antagonists, integrase inhibitors and maturation inhibitors. CCR5 antagonists are thought to inhibit HIV-1 entry into host cells by occupying a specific site on the CCR5 receptor, preventing attachment of the HIV-1 envelope protein gp120. Integrase inhibitors are small synthetically prepared molecules that block RNA/DNA interactions and modify protein or enzyme synthesis. Data on the pharmacokinetics and pharmacodynamics of these new antiretroviral agents continue to generate interest. This review reports the known data on the pharmacokinetics of experimental antiretrovirals, and describe the main drug-drug interactions studied so far.

An NCIC-CTG phase I dose escalation pharmacokinetic study of the matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin.

BACKGROUND: This phase I study was performed to evaluate the safety, tolerability, and efficacy of the oral matrix metalloproteinase inhibitor BAY 12-9566 in combination with doxorubicin in patients with advanced solid tumours, and to identify the maximum tolerated dose of these agents in combination and the dose for use in subsequent studies. PATIENTS AND METHODS: 14 patients were entered onto 3 dose levels consisting of escalating doses of doxorubicin (50 mg/m(2), 60 mg/m(2) and 70 mg/m(2)) with 800 mg po bid BAY 12-9566. At all three dose levels, patients received doxorubicin alone in cycle one on day 1. Daily oral dosing with BAY 12-9566 was started on day 8 of cycle 1, and thus doxorubicin was given concurrently with BAY 12-9566 in cycle 2. Patients were continued on treatment until a dose limiting toxicity or tumour progression occurred. RESULTS: Pharmacokinetic studies from cycles 1 and 2 from the patients treated in the first three dose levels demonstrated that the addition of BAY 12-9566 increased the AUC(0-12h) levels of doxorubicin by a median of 48%. No effects were seen on the BAY 12-9566 pharmacokinetic values. Two dose limiting toxicities were seen at the third dose level. One patient experienced grade 3 stomatitis in cycle 2, and another patient experienced grade 4 granulocytopenia in cycle 1 and grade 4 thrombocytopenia in cycle 2. Thus the maximum tolerated dose of 60 mg/m(2) was declared. These toxicities were those that would have been expected from doxorubicin alone. CONCLUSIONS: BAY 12-9566 can be safely administered with full doses of doxorubicin without evidence of clinical interaction. The recommended dose of doxorubicin to be combined with BAY 12-9566 800 mg po b.i.d is 60 mg/m(2), however, further development of BAY 12-9566 has been abandoned.

Aqueous and cosolvent solubility data for drug-like organic compounds.

Recently 2 QSPR-based in silico models were developed in our laboratories to predict the aqueous and non-aqueous solubility of drug-like organic compounds. For the intrinsic aqueous solubility model, a set of 321 structurally diverse drugs was collected from literature for the analysis. For the PEG 400 cosolvent model, experimental data for 122 drugs were obtained by a uniform experimental procedure at 4 volume fractions of PEG 400 in water, 0%, 25%, 50%, and 75%. The drugs used in both models represent a wide range of compounds, with log P values from -5 to 7.5, and molecular weights from 100 to >600 g/mol. Because of the standardized procedure used to collect the cosolvent data and the careful assessment of quality used in obtaining literature data, both data sets have potential value for the scientific community for use in building various models that require experimental solubility data.

Preclinical pharmacology of lumiracoxib: a novel selective inhibitor of cyclooxygenase-2.

1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified COX-1 and COX-2 with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for COX-2 and 67 microM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B(2) (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7. Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety.

Pharmacology and gastrointestinal safety of lumiracoxib, a novel cyclooxygenase-2 selective inhibitor: An integrated study.

BACKGROUND AND AIMS: Lumiracoxib is a structurally novel, acidic selective inhibitor of cyclooxygenase (COX)-2. We coordinated existing methodologies in a single study to evaluate potency, selectivity, and effect on the human gastrointestinal tract. METHODS: Twenty four healthy subjects (aged 18-45 years, 12 female) received high dose lumiracoxib (800 mg every day), standard dose naproxen (500 mg twice a day), or placebo for 8 days in a double-blind randomized crossover study. At the start and end of each dosing period, COX-2 selectivity was assessed by ex vivo serum thromboxane B(2) (COX-1) and lipopolysaccharide stimulated prostaglandin (PG) E(2) (COX-2), mucosal injury by endoscopy, and small and large bowel permeability by 0- to 5-hour and 5- to 24-hour (51)Cr-EDTA absorption. Plasma lumiracoxib was measured 2 hours after dosing on day 8 and vortex-stimulated ex vivo gastric mucosal PGE(2) synthesis at the end of each treatment period by enzyme immunoassay. RESULTS: Lumiracoxib was well absorbed and demonstrated similar potency to naproxen as a COX-2 inhibitor (77% and 66% inhibition, respectively, vs. placebo), but it differed in being more selective (24% and 97% inhibition of thromboxane B(2) vs. placebo). Gastric PGE(2) was reduced by 69% by naproxen (P < 0.001 vs. placebo) and 29% by lumiracoxib (P < 0.01 vs. placebo and naproxen). No subjects developed gastroduodenal erosions on lumiracoxib (vs. 75% on naproxen and 12.5% on placebo). (51)Cr-EDTA absorption increased significantly with naproxen but not lumiracoxib. CONCLUSIONS: Lumiracoxib is a potent selective inhibitor of COX-2 that causes little or no endoscopically detected stomach or duodenal injury or changes in bowel permeability.

Comparison of the response of three microalgae species exposed to elutriates of estuarine sediments based on growth and chemical speciation.

The elutriate sediment toxicity test (ESTT) provides a measure of the amount of a substance that is exchanged between the sediment and the aqueous phase during resuspension processes such as floods or dredging operations. This study used ESTT with two complementary aims: a comparison of the elutriates of two estuarine sediments (anaerobic muddy [A] and aerobic sandy [B]) in terms of toxicity and a comparison of the response of three different microalgae (Emiliania huxleyi (coccolithophore), Dunaliella minuta (green alga), and Phaeodactylum tricornutum (diatom)) to each elutriate in terms of growth, heavy metals uptake, and organic ligands release or uptake in order to find eventual differences of sensitivity. The interpretation of the results was based on chemical speciation in the culture media. Both elutriates, particularly A, were much richer than seawater (control medium) in some heavy metals and organic ligands able to bind strongly heavy metals. Elutriate A slightly inhibited P. tricornutum growth but stimulated growth of E. huxleyi and D. minuta. Elutriate B stimulated the growth of the three algal species. Therefore, the diatom behaved differently from both the coccolithophore and the green alga. Strong complexation of trace metals by organic ligands could be the cause of absence of the metallic toxicity of the elutriates. Growth inhibition of P. tricornutum in elutriate A could be caused by ammonia-N and/or organic compounds. The concentration of the organic ligands decreased markedly (about 75%) in both elutriates after 10 d of incubation in contrast to the control culture, where their concentration increased about 50% because of exudation. This phenomenon was interpreted to result from ligand uptake by the algae, free or as metal complexes. This work demonstrated that beside the evaluation of toxicity of free heavy metals to alga species, the organic ligands must not be ignored. Depending on the amount of ligand present, the toxicity can be reduced (sequestration) or enhanced (better availability through uptake of metal-ligand complexes). Since the applied ESTT is a standard procedure (U.S. Environmental Protection Agency) for the evaluation of dredged material proposed for ocean disposal, it is necessary to discuss results obtained during toxicity tests with such elutriates in detail.

Benefit and risk of organic ultraviolet filters.

Modern sunscreen products provide broad-spectrum UV protection and may contain one or several UV filters. A modern UV filter should be heat and photostable, water resistant, nontoxic, and easy to formulate. Identification of a substance that meets these criteria is as difficult as discovering a new drug; hundreds of new molecules are synthesized and screened before a lead candidate is identified. The most important aspect in the development of a new UV filter is its safety. In our laboratories, the safety of new ultraviolet filters is assessed by an initial in vitro screen including photostability, cytotoxicity, photocytotoxicity, genotoxicity, and photogenotoxicity tests. These tests are performed in mammalian, yeast, and bacterial cell systems. Skin penetration potential is measured in vitro using human skin or, when required by regulations, in vivo. Because modern sunscreens are selected on the basis of their retention on and in the stratum corneum and are formulated as poorly penetrating emulsions, they generally have very low to negligible penetration rates. The safety and efficacy of UV filters are regulated and approved by national and international health authorities. Safety standards in the European Union, United States, or Japan stipulate that new filters pass a stringent toxicological safety evaluation prior to approval. The safety dossier of a new UV filter resembles that of a new drug and includes acute toxicity, irritation, sensitization, phototoxicity, photosensitization, subchronic and chronic toxicity, reproductive toxicity, genotoxicity, photogenotoxicity, carcinogenicity, and, in the United States, photocarcinogenicity testing. The margin of safety of new UV filters for application to humans is estimated by comparing the potential human systemic exposure with the no-effect level from in vivo toxicity studies. Only substances with a safe toxicological profile and a margin of safety of at least 100-fold are approved for human use. Finally, prior to marketing, new UV filters undergo stringent human testing to confirm their efficacy as well as the absence of irritation, sensitization, photoirritation, and photosensitization potential in man. UV filters not only protect against acute skin injury, such as sunburn, but also against long-term and chronic skin damage, including cellular DNA damage, photoinduced immune suppression, and, by extension, skin cancer. The protection provided by modern sunscreens against UV-induced skin cancer was shown in animal photocarcinogenicity studies and confirmed by numerous in vitro, animal, and human investigations: UV filters protect the p53 tumor suppressor gene from damage and prevent UV-induced immune suppression. Recent studies suggest that sunscreens protect against precursor lesions of skin cancer, such as actinic keratoses. Additional benefits of ultraviolet filters include prevention of photodermatoses, such as polymorphic light eruption, and, possibly, photoaging. Modern sunscreens are safe for children and adults. Percutaneous penetration and irritation rates of topically applied substances in children and adults are similar. The principal protective measure is to keep children out of the sun and/or to cover them with protective clothes; however, sunscreens are a safe and effective and often the only feasible defense of children against UV radiation. In conclusion, sunscreens are safe protective devices that undergo stringent safety and efficacy evaluation.

Phosphorus characteristics of settling and suspended particles in Lake Erken.

The aim of the study was to determine proportions of phosphorus forms as well as total phosphorus content in suspended and settling particles during spring, summer and autumn in order to improve the understanding of particle composition and mineralization processes in moderately eutrophic, temperate lakes with summer stratification. The highest phosphorus content was found in epilimnetic suspended matter with maximum mean concentration in summer. There was a gradual decrease in total P content from suspended matter to settling particles and surficial sediment. Phosphorus extracted with sodium hydroxide was the dominant fraction showing organic phosphorus to be most important. Labile phosphorus was a significant fraction and contributed more in epilimnetic suspended matter and in material from the uppermost traps in comparison to hypolimnetic material and surficial sediment. There was a seasonal variation in P forms with maximal shares of labile P and organic P in summer. The findings clearly indicate a dominance of phytoplankton and detritus in the epilimnetic particulate matter during summer, while inorganic and resuspended material is more important during mixing periods. The P composition of settling particles and suspended matter show similar trends, but the total content and shares of labile and organic P are significantly higher in the latter.

Empirical relations predicting human and rat tissue:air partition coefficients of volatile organic compounds.

Based on the hypothesis that tissue partitioning of volatile organic compounds (VOCs) is due to lipophilic and hydrophilic interactions with tissue components, empirical relations are established between olive oil (P(oil:air)), saline (P(saline:air)), and tissue partition coefficients (P(tissue:air)) for human and rat tissues. Reported values of partition coefficients of a wide range of VOCs with distinct chemical structures (n = 137) have been compiled from the literature. Bilinear regression analysis shows that partition coefficients of VOCs in human blood, brain, fat, liver, kidney, and muscle tissues are well described by a linear combination of P(oil:air) and P(saline:air) with tissue-specific regression coefficients. The regression coefficient associated with the hydrophilic component of VOC partitioning in rat tissues is systematically higher than that of human tissues. For the human model, tissue concentrations calculated from predicted partition coefficients are generally within a factor 4 of tissue concentrations calculated from experimentally observed partition coefficients. These results demonstrate that, without prior knowledge of tissue composition, it is possible to obtain estimates of human tissue partition coefficients of VOCs with an accuracy that is in the same range as that commonly used in risk assessment.