Thiophene Carboxamide Analogs with Long Alkyl Chains Comprising Ethylene Glycol Units Inhibit Glioblastoma Cell Proliferation by Activating AMPK.

Glioblastoma is a refractory malignant tumor that requires novel therapeutic strategies for effective treatment. We have previously reported that JCI-20679 (1), an analog of annonaceous acetogenins, shows potent antitumor activity against glioblastomas. However, the synthesis of 1 requires 23 steps, including 16 steps for the preparation of a tetrahydrofuran (THF) moiety. This study reports the design and synthesis of 11 analogs with a triethylene glycol moiety in place of the THF moiety in 1. Among these, the analog 2k with an n-decyl chain exhibited potent inhibitory activity against the growth of glioblastoma stem cells by inhibiting mitochondrial function and synergistically enhancing the effect of temozolomide (TMZ). Furthermore, 2k significantly suppressed tumor growth without critical toxicity in vivo. Hence, this study presents novel potential anticancer agents and a strategy for the development of these agents that can be produced easily.

Exploration of ethylene glycol linked nitrofurantoin derivatives against Leishmania: Synthesis and in vitro activity.

Leishmaniasis is a neglected tropical disease that is caused by the Leishmania parasite. It is estimated that there are more than 350 million people at risk of infection annually. Current treatments that are in clinical use are expensive, have toxic side effects, and are facing parasitic resistance. Therefore, new drugs are urgently required. In the quest for new, safe, and cost-effective drugs, a series of novel ethylene glycol derivatives of nitrofurantoin was synthesised and the in vitro antileishmanial efficacy of the compounds tested against Leishmania donovani and Leishmania major strains. Arylated ethylene glycol derivatives were found to be the most potent, with submicromolar activity up to 294-fold greater than the parent compound nitrofurantoin. Analogues 2j and 2k had the best antipromastigote activities with submicromolar IC50 values against L. major IR-173 and antimonial-resistant L. donovani 9515 strains.

Effect of supplementation of cryoprotectant solution with hydroxypropyl cellulose for vitrification of bovine oocytes.

BACKGROUND: Successful cryopreservation of bovine oocytes is very important for research and commercial applications. However, the survival and development rate of vitrified-thawed (VT) oocytes are lower than those of non-vitrified-thawed (non-VT) oocytes. OBJECTIVE: To investigate the effect of adding hydroxypropyl cellulose (HPC) to the vitrification solution for bovine oocytes. MATERIALS AND METHODS: For vitrification, bovine metaphase II oocytes were pretreated with a solution containing 10% ethylene glycol supplemented with 0, 10, 50, or 100 ug/mL HPC for 5 min, exposed to a solution containing 30% ethylene glycol supplemented with 0, 10, 50, or 100 ug/mL HPC for 30 s, and then directly plunged into liquid nitrogen. RESULTS: The survival rate of oocytes was significantly higher in the 50 HPC group than in the 0, 10, and 100 HPC groups. The reactive oxygen species level was lower in the non-VT and 50 HPC groups than in the other groups. The mRNA levels of proapoptotic genes (Bax) were lower in the non-VT, 0, and 50 HPC groups than in the other groups. The mRNA levels of antiapoptotic genes (BCl2) were higher in the non-VT than in the other groups. The development rates of embryos (day 8) obtained via parthenogenetic activation (PA) were determined in the non-VT, 0 HPC, and 50 HPC groups. The cleavage rate was significantly higher in the non-VT group. CONCLUSION: Supplementation of vitrification solution with HPC improves the survival of VT bovine oocytes and the development capacity of embryos derived from these oocytes via PA. doi.org/10.54680/fr23110110212.

Synthesis and antineoplastic activity of ethylene glycol phenyl aminoethyl ether derivatives as FOXM1 inhibitors.

FOXM1 signalling pathways are highly expressed in multiple human cancers. Based on the crystal structure of the FOXM1 DNA binding domain, our preliminary research found ethylene glycol (4-benzyloxyphenyl) cyclopentylaminoethyl ether XST20, which could inhibit ovarian cancer cell proliferation and showed a medium affinity for the truncated protein FOXM1. This study intended to develop a FOXM1 inhibitor with stronger affinity and higher efficiency to be utilized as a molecular tool and drug candidate. We evaluated the optimization direction through molecular docking and systematically modified the structure of XST20. A novel class of ethylene glycol phenyl aminoethyl ether derivatives were synthesized, their anticancer activity and mechanism were evaluated, and the structure-activity relationship was summarized. Compound S2 showed a stronger affinity for FOXM1 and improved its activity with a broad-spectrum anticancer effect. S2 displayed selective antiproliferative activity against cancer cells with high expression levels of FOXM1 proteins. S2 should be a good chemobiological tool and a potential leading compound for future studies of anticancer drugs targeting FOXM1.

Mussel-Inspired Polymeric Coatings to Realize Functions from Single and Dual to Multiple Antimicrobial Mechanisms.

Numerous efforts to fabricate antimicrobial surfaces by simple yet universal protocols with high efficiency have attracted considerable interest but proved to be particularly challenging. Herein, we designed and fabricated a series of antimicrobial polymeric coatings with different functions from single to multiple mechanisms by selectively utilizing diethylene glycol diglycidyl ether (PEGDGE), polylysine, and poly[glycidylmethacrylate-co-3-(dimethyl(4-vinylbenzyl)ammonium)propyl sulfonate] (poly(GMA-co-DVBAPS)) via straightforward mussel-inspired codeposition techniques. Bactericidal polylysine endowed the modified surfaces with a high ability (∼90%) to kill attached bacteria, while PEGDGE components with unique surface hydration prevented bacterial adhesion, avoiding the initial biofilm formation. Moreover, excellent salt-responsive poly(GMA-co-DVBAPS) enabled reactant polymeric coatings to change chain conformations from shrinkable to stretchable state and subsequently release >90% attached bacteria when treated with NaCl solution, even after repeated cycles. Therefore, the obtained polymeric coatings, polydopamine/poly(GMA-co-DVBAPS) (PDA/PDV), polydopamine/polylysine/poly(GMA-co-DVBAPS) (PDA/l-PDV), and polydopamine/polylysine/poly(GMA-co-DVBAPS)/diethylene glycol diglycidyl ether (PDA/l-PDV-PEGDGE), controllably realized functions from single and dual to multiple antimicrobial mechanisms, as evidenced by long-term antifouling activity to bacteria, high bactericidal efficiency, and salt-responsive bacterial regeneration performance with several bacterial killing-release cycles. This study not only contributes to mussel-inspired chemistry for polymeric coatings with controllable functions but also provides a series of reliable and highly efficient antimicrobial surfaces for potential biomedical applications.

Novel imaging techniques using 18 F-florbetapir PET/MRI can guide fascicular nerve biopsy in amyloid multiple mononeuropathy.

BACKGROUND: Multiple mononeuropathy is a rare presentation of primary (AL) amyloidosis and nerve biopsy is usually needed for diagnosis. Conventional imaging is useful to identify proximal nerve involvement but may be inadequate. We report a patient with multiple mononeuropathy whose presentation was suggestive of AL amyloid neuropathy and in whom repeated tissue biopsies were negative for amyloid (including two sensory nerves and one muscle). METHODS: The patient underwent magnetic resonance imaging (MRI) and whole body 18 F-florbetapir positron emission tomography (PET)/MRI. RESULTS: Whole body 18 F-florbetapir PET/MRI revealed abnormal low-level florbetapir uptake in the right proximal tibial and peroneal nerves, which provided a target for a sciatic bifurcation fascicular nerve biopsy that was diagnostic of AL amyloidosis. CONCLUSIONS: 18 F-florbetapir PET/MRI imaging is a promising diagnostic tool for patients with suspected peripheral nerve amyloidosis (including multiple mononeuropathy) in whom conventional imaging and nerve and muscle biopsies miss the pathology.

The Potential Risk Assessment of Phenoxyethanol with a Versatile Model System.

In this study, the toxic effects of phenoxyethanol (Phy-Et), which is widely used in cosmetic industry, has been investigated with Allium test by means of physiological, cytogenetic, anatomical and biochemical parameters. To determine the changes in physiological reactions weight gain, relative injury rate, germination percentage and root length were investigated. Malondialdehyde, superoxide dismutase, glutathion and catalase levels were analyzed as biochemical parameters for determining the presence of oxidative stress. Mitotic index, micronucleus and chromosomal abnormality frequencies were studied as cytogenetic evaluation and the anatomical changes in root tip cells were investigated by cross sections. Changes in surface polarity and wettability were investigated by taking contact angle measurements of pressed root preparations. The mechanism of toxicity has been tried to be explained by these contact angles and this is the first study using contact angle measurements in toxicity tests. Consequently, exposure to Phy-Et resulted in a decrease in all measured physiological parameters and in mitotic index. In contrast, significant increases in the micronucleus and chromosomal abnormality frequencies were observed and the most significant toxic effect was found in 10 mM Phy-Et treated group. Phy-Et application induced oxidative damage and caused a significant increase in malondialdehyde level and a decrease in glutathione level compared to control group. Also a response occured against oxidative damage in superoxide dismutase and catalase activity and the activities increased in 2.5 mM and 5 mM Phy-Et treated groups and decreased in 10 mM Phy-Et treated groups. Furthermore, Phy-Et treatment resulted in some anatomical damages and changes such as necrosis, cell deformation and thickening of the cortex cell wall in root tip meristem cells of A. cepa. In the contact angle measurements taken against water, it was found that the wettability and hydrophilicity of the root preparations treated with Phy-Et were reduced, and this was the explanation of the growth abnormalities associated with water uptake. As a result, it was found that Phy-Et application caused toxic effects on many viability parameters and A. cepa test material was a reliable biomarker in determining these effects.

Evaluation of [18F]-N-Methyl lansoprazole as a Tau PET Imaging Agent in First-in-Human Studies.

Development of positron emission tomography (PET) imaging agents capable of quantifying tau aggregates in neurodegenerative disorders such as Alzheimer's disease (AD) is of enormous importance in the field of dementia research. The aim of the present study was to conduct first-in-man imaging studies with the potential novel tau imaging agent [18F]N-methyl lansoprazole ([18F]NML). Herein we report validation of the synthesis of [18F]NML for clinical use by labeling the trifluoromethyl group via radiofluorination of the corresponding gem-difluoro enol ether precursor. This is the first use of this method for clinical production of PET radiotracers and confirmed that it can be readily implemented at multiple production facilities to provide [18F]NML in good noncorrected radiochemical yield (3.4 ± 1.5 GBq, 4.6% ± 2.6%) and molar activity (120.1 ± 186.3 GBq/µmol), excellent radiochemical purity (>97%), and suitable for human use (n = 15). With [18F]NML in hand, we conducted rodent biodistribution, estimates of human dosimetry, and preliminary evaluation of [18F]NML in human subjects at two imaging sites. Healthy controls (n = 4) and mildly cognitively impaired (MCI) AD patients (n = 6) received [18F]NML (tau), [18F]AV1451 (tau), and [18F]florbetaben or [18F]florbetapir (amyloid) PET scans. A single progressive supranuclear palsy (PSP) patient also received [18F]NML and [18F]AV1451 PET scans. [18F]NML showed good brain uptake, reasonable pharmacokinetics, and appropriate imaging characteristics in healthy controls. The mean ± SD of the administered mass of [18F/19F]NML was 2.01 ± 2.17 µg (range, 0.16-8.27 µg) and the mean administered activity was 350 ± 62 MBq (range, 199-403 MBq). There were no adverse or clinically detectable pharmacologic effects in any of the 11 subjects, and no significant changes in vital signs were observed. However, despite high affinity for tau in vitro, brain retention in MCI/AD and PSP patients was low, and there was no evidence of specific signals in vivo that corresponded to tau. Although it is still unclear why clinical translation of the radiotracer was unsuccessful, we nevertheless conclude that further development of [18F]NML as a tau PET imaging agent is not warranted at this time.

Gel-based Microemulsion Design and Evaluation for Topical Application of Rivastigmine.

OBJECTIVE: The aim of the present study was to design nanocarriers for the topical application of rivastigmine. METHODS: The effect of cosurfactants, hydrophilic gel and loading amount on the permeability of rivastigmine through rat skin was evaluated. Skin irritation tests and stability tests were performed to evaluate the utility of tested formulations. RESULTS: The results showed that the microemulsion formation and characteristics of drug-loaded formulations were related to many parameters of the components. When using microemulsion systems as a vehicle, the permeation rate remarkably increased about 13.2~24.3-fold and the lag time was significantly shortened from 24 h to 4.7 h. Formulations containing a cosurfactant of Diethylene Glycol Monobutyl Ether (DEGBE) showed higher enhancement effect, while increasing the loading dose from 0.5% to 5% further increased the flux about 2.1-fold and shortened the lag time. CONCLUSION: The drug-loaded experimental formulation did not cause skin irritation and had good stability at 20ºC and 40ºC storage for at least 3 months. The result showed that gel-based microemulsion formulation could be a promising approach for topical administration.

Tailor-Engineered POSS-Based Hybrid Gels for Bone Regeneration.

Organic-inorganic oligo(ethylene glycol)-polyhedral oligomeric silsesquioxanes (OEGn-POSS) hybrid materials are woven into macroscopically shaped entities by thiol-ene chemistry. The mechanical behavior and interfacial nature of the OEGn-POSS materials are easily tailored by changing the length of OEGn. The nanostructured OEGn-POSS materials exhibited excellent bioactivity to form hydroxyapatite, whose morphology was also dependent on the molecular weight of OEGn. Among them, OEG2-POSS materials enhanced the in vitro differentiation of adipose-derived stem cells to osteoblasts and promoted the in vivo bone formation within a femoral condyle defect site, but they could be limited by the mismatch rates between the degradation and new bone formation. Thus, OEG2-POSS could be practically applied for bone regeneration by optimizing the degradation rate based on its key structural features, which would be of great benefit to bone tissue engineering in the future.

Disulfide-Mediated Bioconjugation: Disulfide Formation and Restructuring on the Surface of Nanomanufactured (Microfluidics) Nanoparticles.

This study is about (1) nanomanufacturing (focusing on microfluidic-assisted nanoprecipitation), (2) advanced colloid characterization (focusing on field flow fractionation), and (3) the possible restructuring of surface disulfides. Disulfides are dynamic and exchangeable groups, and here we specifically focus, first, on their use to introduce biofunctional groups and, second, on their re-organization, which may lead to variable surface chemistries and uncontrolled cell interactions. The particles were obtained via microfluidic-assisted (flow-focused) nanoprecipitation of poly(ethylene glycol)-b-poly(ε-caprolactone) bearing or not a 2-pyridyl disulfide (PDS) terminal group, which quantitatively exchanges with thiols in solution. In this study, we have paid specific attention to size characterization, thereby also demonstrating the limitations of dynamic light scattering (DLS) as a stand-alone technique. By using asymmetric flow field flow fractionation coupled with DLS, static light scattering (SLS), and refractive index detectors, we show that relatively small amounts of >100 nm aggregates (cryogenic transmission electron microscopy and SLS/DLS comparison suggesting them to be wormlike micelles) dominated the stand-alone DLS results, whereas the "real" size distributions picked <50 nm. Our key result is that the kinetics of the conjugation based on PDS-thiol exchange was controlled by the thiol pKa, and this also determined the rate of the exchange between the resulting disulfides and glutathione (GSH). In particular, more acidic thiols (e.g., peptides, where a cysteine is flanked by cationic residues) react faster with PDS, but their disulfides hardly exchange with GSH; the reverse applies to thiols with a higher pKa. Disulfides that resist against restructuring via thiol-disulfide exchange allow for a stable bioconjugation, although they may be bad news for payload release under reducing conditions. However, experiments of both thiol release and nanoparticles uptake in cells (HCT116) show that also the disulfides formed from less-acidic and, therefore, less-reactive, and more exchangeable thiols were stable for at least a few hours even in a GSH-rich (10 mM) environment; this suggests a sufficiently long stability of surface groups to achieve, for example, a cell-targeting effect.

Comparison of TEMPO® BC with Spiral Plating Methods for the Enumeration of Bacillus cereus in Cosmetic Products Either Naturally Preserved or Preserved with Phenoxyethanol.

Background: The U.S. Food and Drug Administration's (FDA) Bacteriological Analytical Manual (BAM) uses Bacillus cereus rapid agar (BACARA) and Mannitol-yolk-polymyxin (MYP) agar for the enumeration of the members of B. cereus group. Objective: The automated TEMPO Most Probable Number system was compared with the FDA BAM method for the detection of B. cereus group members in cosmetic products. Methods: We inoculated a range of cosmetic products with pure B. cereus spore suspensions (density = 0.5 McFarland) at high (6 log CFU/mL), medium (5 log CFU/mL), and low (4 log CFU/mL) levels. Test portions were aged for 72 h. Five replicates per sample were analyzed; uninoculated test portions served as controls. We also evaluated whether TEMPO BC erroneously detected non-B. cereus or other adulterant organisms. Results: No significant differences (P > 0.05) were found among the TEMPO BC and the BAM spiral plating methods. Correlations between TEMPO BC - BACARA and TEMPO BC - MYP were 0.895 and 0.893 for powder type products, 0.834 and 0.846 for cream and oil-based products, and 0.929 and 0.923 for liquid products, respectively. Non-B. cereus strains were not detected by TEMPO BC. Conclusions: The TEMPO BC method can be used for the detection of B. cereus in cosmetic products without preservatives, or those preserved with either phenoxyethanol or other organic substances.

Correlation of antimicrobial effects of phenoxyethanol with its free concentration in the water phase of o/w-emulsion gels.

Antimicrobial testing is a time consuming and cost-intensive but essential method for evaluation of newly developed pharmaceutical formulations for topical use. In this study the correlation between free preservative concentration in emulsion gels measured by equilibrium dialysis and the successful preservative effectiveness testing for Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis (analyzed according to Ph. Eur. and USP) was investigated. The higher the lipophilicity of the oil phase and the lower the content of the aqueous phase with regard to dissolved ingredients the more preferably distributed is phenoxyethanol to the water phase and, consequently, the higher was the efficacy against the microbes. Increased emulsifier concentrations reduced the free amount of the preservative due to micellar interactions. Aspergillus brasiliensis was the most resistant and Staphylococcus aureus the most sensitive germ towards phenoxyethanol in o/w-emulsion gels.

Use of the PET ligand florbetapir for in vivo imaging of pancreatic islet amyloid deposits in hIAPP transgenic mice.

AIMS/HYPOTHESIS: Islet amyloid deposits contribute to beta cell dysfunction and death in most individuals with type 2 diabetes but non-invasive methods to determine the presence of these pathological protein aggregates are currently not available. Therefore, we examined whether florbetapir, a radiopharmaceutical agent used for detection of amyloid-ß deposits in the brain, also allows identification of islet amyloid in the pancreas. METHODS: Saturation binding assays were used to determine the affinity of florbetapir for human islet amyloid polypeptide (hIAPP) aggregates in vitro. Islet amyloid-prone transgenic mice that express hIAPP in their beta cells and amyloid-free non-transgenic control mice were used to examine the ability of florbetapir to detect islet amyloid deposits in vitro, in vivo and ex vivo. Mice or mouse pancreases were subjected to autoradiographic, histochemical and/or positron emission tomography (PET) analyses to assess the utility of florbetapir in identifying islet amyloid. RESULTS: In vitro, florbetapir bound synthetic hIAPP fibrils with a dissociation constant of 7.9 nmol/l. Additionally, florbetapir bound preferentially to amyloid-containing hIAPP transgenic vs amyloid-free non-transgenic mouse pancreas sections in vitro, as determined by autoradiography (16,475 ± 5581 vs 5762 ± 575 density/unit area, p < 0.05). In hIAPP transgenic and non-transgenic mice fed a high-fat diet for 1 year, intravenous administration of florbetapir followed by PET scanning showed that the florbetapir signal was significantly higher in amyloid-laden hIAPP transgenic vs amyloid-free non-transgenic pancreases in vivo during the first 5 min of the scan (36.83 ± 2.22 vs 29.34 ± 2.03 standardised uptake value × min, p < 0.05). Following PET, pancreases were excised and florbetapir uptake was determined ex vivo by γ counting. Pancreatic uptake of florbetapir was significantly correlated with the degree of islet amyloid deposition, the latter assessed by histochemistry (r = 0.74, p < 0.001). CONCLUSIONS/INTERPRETATION: Florbetapir binds to islet amyloid deposits in a specific and quantitative manner. In the future, florbetapir may be useful as a non-invasive tool to identify islet amyloid deposits in humans.

Modulation of rainbow trout (Oncorhynchus mykiss) cutaneous mucosal immune responses following anesthesia: A comparative study on different anesthetic agents.

The present study investigated the possible effects of different anesthetic agents including MS222 (50 ppm), 2-Phenoxyethanol (2-PE) (0.2 mL L-1) and clove oil (25 ppm), on cutaneous mucosal immune parameters in rainbow trout (Oncorhynchus mykiss). The induction and recovery times for each anesthetic agent were assessed. Also, the immune parameters were measured in skin mucus, 1 and 24 h post anesthesia. No significant difference was observed among treatments at 1 h post-anesthesia except for bactericidal and alkaline phosphatase (ALP) activities which was significantly enhanced in fish exposed to 2-PE compared to other anesthetics. At 24 h post-anesthesia, most of the skin mucosal immune parameters were increased upon exposure to clove oil but decreased following exposure to 2-PE. However, no significant change was noticed after MS222 exposure. These results demonstrated that the anesthetics type should be considered to avoid possible immunosuppression in farmed fish. Furthermore, the present results could be useful for better understanding of alterations in cutaneous mucosal immunity in response to chemical stressors such as anesthetic agents.

In vitro nuclear receptor inhibition and cytotoxicity of hydraulic fracturing chemicals and their binary mixtures.

The widespread use of hydraulic fracturing (HF) in oil and gas extraction operations has led to concern over environmental risks posed by chemicals used in HF fluids. Here we employed a suite of stable luciferase reporter gene assays to investigate the potential for selected HF chemicals or geogenics to activate or antagonise nuclear receptor signalling. We screened three biocides (bronopol [BP], glutaraldehyde [GA], and tetrakis(hydroxymethyl)phosphonium sulfate [THPS]), a surfactant (2-butoxyethanol), a friction reducer (polyacrylamide), and a coal seam geogenic (o-cresol) for their potential to act as agonists or antagonists of the estrogen receptor, androgen receptor, progesterone receptor (PR), glucocorticoid receptor or peroxisome proliferator-activated receptor gamma (PPARγ). None of the chemicals induced luciferase activity in any of assays used in the study. In antagonistic mode, BP, GA and THPS caused reductions in luciferase activity in the reporter assays at higher concentrations (50-100 µM), while at low concentrations (2-10 µM) GA and THPS enhanced luciferase activity in some assays relative to controls. None of the other tested chemicals exhibited antagonism in the selected assays. In most cases, altered receptor signalling only occurred at concentrations exhibiting cytotoxicity. However, PPARγ activity, and to a lesser extent PR activity, were inhibited by THPS at sub-cytotoxic concentrations. The majority of binary combinations tested exhibited significantly less-than-additive cytotoxicity, and none of the combinations exhibited synergistic cytotoxicity. In summary, the results of the present study indicate that the selected chemicals are not likely to function as direct agonists of the nuclear receptors tested, and only one chemical, THPS was an apparent partial antagonist of two nuclear receptors.

Florbetapir-PET ß-amyloid imaging and associated neuropsychological trajectories in survivors of critical illness: A case series.

PURPOSE: Cognitive impairment resembling Alzheimer's disease is common in survivors of critical illness. We hypothesized that Intensive Care Unit (ICU) survivors with cognitive impairment would have significant amyloid and designed a pilot study to explore this relationship. MATERIALS AND METHODS: A pilot, case series of a convenience sample of 14 adult medical and surgical ICU survivors, in a clinical neuroradiology clinic. Patients underwent cognitive testing at 3months, 1year, 4years, and 6years after hospital discharge with the Repeatable Battery for the Assessment of Neuropsychological Status. They received a single PET scan using amyloid PET imaging (florbetapir F18) 2 to 4years after their ICU stay. RESULTS: Amyloid (defined as a Standard Uptake Value ratio or SUVr >1.10) was present in 2 of 14 (14%) individuals, both of whom demonstrated significant cognitive impairment yet no consistent decline over time. Of the 6 impaired patients (RBANS<78), 4 (66.7%) were amyloid negative. CONCLUSIONS: It is feasible to assess ICU survivors with amyloid imaging. In this small sample, most patients with cognitive impairment were negative on amyloid PET imaging, which raises the possibility that ICU survivors may experience a unique form of dementia not driven by an amyloid related mechanism.

Upgrading of dissolution and anti-hypertensive effect of Carvedilol via two combined approaches: self-emulsification and liquisolid techniques.

OBJECTIVE: The aim of the study was to design a self-emulsifying drug delivery system (SEDDS) of the anti-hypertensive Carvedilol in liquid and liquisolid forms as a way to enhance its dissolution profile and anti-hypertensive effect. METHODS: Solubility studies of Carvedilol in various oils, surfactants and co-surfactants were conducted, followed by the construction of pseudo-ternary phase diagrams and other in vitro assessments. The selected SEDDS formulation (S1) was adsorbed onto solid powder excipients and compressed into tablets. The resulting liquisolid tablets were evaluated under British Pharmacopoeia (B.P.) specifications. Pre- and post-compression studies were performed to determine the flow properties and evaluate the liquisolid systems, followed by in vivo studies in hypertensive rats. RESULTS: Attempts of self-emulsification, droplet size, and thermodynamic stability studies showed acceptable results for the S1 formulation containing Capryol 90, Tween 20, and Transcutol HP (10:53.3:26.2%), respectively. Pre-compression studies showed adequate flowability and compatibility of liquid and solid excipients with Carvedilol. The selected liquisolid tablet (LS7) demonstrated the best disintegration and water absorption ratio in addition to satisfactory friability and hardness. A significantly (p < .05) fast dissolution rate was observed for both SEDDS and liquisolid formulations when compared to pure drug and marketed Carvepress®. The in vivo study of LS7 formulation revealed a rapid significant (p < .01) decrease in the mean arterial pressure (MAP) of the rats (112.72 mmHg) within the first 30 min followed by a further decline (107.22 mmHg) after 1 h when compared to Carvepress®. CONCLUSION: Self-emulsifying liquisolid tablets expressed rapid onset of action with enhanced anti-hypertensive effect of Carvedilol.

The effect of diethylene glycol monoethyl ether on skin penetration ability of diclofenac acid nanosuspensions.

The poor ability of many drugs to cross skin layers is the main limiting factor for the exploitation of the transdermal route for drug delivery. As a consequence, several approaches have been proposed to overcome the skin barrier, such as the inclusion of penetration enhancers in the topically applied drug solutions and emulsions. In this work, the penetration enhancer diethylene glycol monoethyl ether was included in novel diclofenac acid nanocrystal formulations, developed using the wet media milling technique and Poloxamer 188 as stabilizer. The nanosuspensions were characterized by different techniques such as scanning electron microscopy, differential scanning calorimetry, X-ray powder diffractometry, Fourier-transform infrared spectroscopy and photon correlation spectroscopy. The influence of diethylene glycol monoethyl ether on (trans)dermal delivery of diclofenac nanosuspensions was evaluated by in vitro studies using Franz diffusion cells and pig skin. RESULTS: demonstrated that the presence of diethylene glycol monoethyl ether influences the Poloxamer 188 ability to stabilize the nanocrystals during the milling process, leading to larger particles as compared to penetration enhancer-free nanosuspensions. As previously reported, the in vitro permeation studies indicate the nanosizing as a key factor in the dermal penetration of topically applied diclofenac. Surprisingly enough, the inclusion of increasing amounts of the penetration enhancer in the formulation decreased the diclofenac accumulation in the stratum corneum, while showing no significant effect on the drug delivered to the epidermis. Overall, the present results exclude a synergistic effect of the nanosizing approach and the addition of diethylene glycol monoethyl ether in regard to the skin penetration of diclofenac applied as a nanosuspension.

Sub-Acute Toxicity Study of Ethylene Glycol Monomethyl Ether on the Antioxidant Defense System of the Testes and Epididymes of Wistar Rats.

Ethylene glycol monomethyl ether is a toxicant with wide industrial applications. This study is aimed atinvestigating its effect on the antioxidant system of the reproductive organs of male rats. Fifty male Wistar rats weredistributed into five groups. Group I received distilled water, Groups II-V received EGME at 100, 200, 300 and 400 mg/kgbody weight respectively. All administrations were done orally for fourteen days and the weight was monitored weekly. Onday fifteen, the animals were sacrificed and reproductive organs were collected and weighed. The testes and epididymeswere processed for the biochemical estimations, histopathology and spermatozoa analysis. The percentage body weightgained weekly and the relative weight of the testes reduced significantly (p < 0.05) in the treatment groups. The spermatozoaanalysis showed decreases in the treatment groups. In the testis and epididymis, various antioxidant parameters such assuperoxide dismutase and glutathione-S-transferase were affected. The histopathology results confirmed the biochemicalfindings. The study suggests that EGME exerts deleterious effects on the testes and epididymes by increasing the oxidativeload in rats.