Polymorphic behaviour of Compritol®888 ATO as bulk lipid and as SLN and NLC

Compritol®888 ATO (glycerol behenate) is widely used as a pharmaceutical excipient in the field of solid dosage forms due to its lubricating properties. It is an amphiphilic material with a high melting point (～70°C) and, therefore, it can also be used to prepare aqueous colloidal dispersions. The aim of this paper is to study the suitability of Compritol®888 ATO for the production of solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) for the entrapment of a lipophilic model drug. This study assesses the crystalline structure of the bulk lipid, as well as the changes that occur in its crystal lattice with the addition of ‘impurities’, such as oil (α-tocopherol) and drug (ketoconazole), using DSC and X-ray diffraction analysis before and after thermal stress. Aqueous SLN and NLC dispersions were produced using an appropriate surfactant/co-surfactant system and their physicochemical stability was assessed by PCS, LD, DSC and by WAXS. It was found that the crystalline lattice of Compritol®888 ATO is composed of very small amounts of the unstable α polymorphic form characteristic of triacylglycerols, which disappears after thermal stress of bulk lipid. Mixing oils and drug molecules which are soluble in this lipid decreased its lattice organization and, thus, was revealed to be suitable for production of lipid nanoparticles containing ketoconazole. However, particle growth could not be avoided during shelf life.     

Identification of contact and respiratory sensitizers according to IL-4 receptor α expression and IL-2 production

Identification of allergenic chemicals is an important occupational safety issue. While several methods exist to identify contact sensitizers, there is currently no validated model to predict the potential of chemicals to act as respiratory sensitizers. Previously, we reported that cytometry analysis of the local immune responses induced in mice dermally exposed to the respiratory sensitizer trimellitic anhydride (TMA 10%) and contact sensitizer dinitrochlorobenzene (DNCB 1%) could identify divergent expression of several immune parameters. The present study confirms, first, that IgE-positive B cells, MHC class II molecules, interleukin (IL)-2, IL-4 and IL-4Rα can differentiate the allergic reactions caused by high doses of strong respiratory (TMA, phthalic anhydride and toluene diisocyanate) and contact sensitizers (DNCB, dinitrofluorobenzene and oxazolone). The second part of the study was designed to test the robustness of these markers when classing the weakly immunogenic chemicals most often encountered. Six respiratory allergens, including TMA (2.5%), five contact allergens, including DNCB (0.25%), and two irritants were compared at doses of equivalent immunogenicity. The results indicated that IL-4Rα and IL-2 can be reliably used to discriminate sensitizers. Respiratory sensitizers induced markedly higher IL-4Rα levels than contact allergens, while irritants had no effect on this parameter. Inversely, contact allergens tended to induce higher percentages of IL-2⁺CD8⁺ cells than respiratory allergens. In contrast, the markers MHC-II, IgE and IL-4 were not able to classify chemicals with low immunogenic potential. In conclusion, IL-4Rα and IL-2 have the potential to be used in classifying a variety of chemical allergens.     

Noble gases as cardioprotectants – translatability and mechanism

Several noble gases, although classified as inert substances, exert a tissue-protective effect in different experimental models when applied before organ ischaemia as an early or late preconditioning stimulus, after ischaemia as a post-conditioning stimulus or when given in combination before, during and/or after ischaemia. A wide range of organs can be protected by these inert substances, in particular cardiac and neuronal tissue. In this review we summarize the data on noble gas-induced cardioprotection, focusing on the underlying protective mechanisms. We will also look at translatability of experimental data to the clinical situation.     

Effects of carbamazepine and metabolites on IL-2, IL-5, IL-6, IL-10 and IFN-γ secretion in epileptic patients: the influence of co-medication

Carbamazepine is a widely used anticonvulsive agent. Its metabolic pathway leads not only to the major active metabolite, carbamazepine-10,11-epoxide, but also to minor terminal metabolites such as iminostilbene and acridine. Carbamazepine is usually well-tolerated, but it may lead to rare, but serious, hypersensitive reactions associated with hypereosinophilia. The mechanisms of hypersensitivity reactions to carbamazepine are still largely unknown, and the implications of the cell-mediated immune response (Th1 pathway) or the humoral immune response (Th2 pathway) are still not understood in these reactions. It is also unclear whether the parent drug or its subsequent metabolites are the primary trigger agent. In our study, we performed ex vivo experiments to evaluate the stimulation of cytokine secretion by carbamazepine, carbamazepine-10,11-epoxide, iminostilbene and acridine. IL-5, IL-6 and IL-10 were quantified as markers of the Th2 pathway, and IL-2 and IFN-γ were used as markers of the Th1 pathway. Blood samples (n=24) were obtained from epileptic patients routinely treated with carbamazepine alone or co-treated with lamotrigine or valproate. The concentrations of cytokines in the plasma were determined before and after 3 h stimulation with drugs. We found a significantly positive effect of co-treatment with valproate on the basal level of IL-5 (p<0.01) and IL-10 (p<0.05). IL-5 production increased only in blood stimulated with a high level of acridine (33 μM), whereas IL-6 production was less specifically stimulated (p<0.05). Because IL-5 is the most potent stimulating factor of the eosinophils, we suggest that the potential helper effect of valproate and acridine can lead to hypersensitive reactions to carbamazepine in the context of the humoral immune response.     

Cyclic hydroxyamidines as amide isosteres: discovery of oxadiazolines and oxadiazines as potent and highly efficacious γ-secretase modulators in vivo

Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aβ(42) in various animal models.     

Is alcohol, tobacco, and cannabis use as well as polydrug use increasing in France?

Two school surveys measured the consumption of alcohol, tobacco and cannabis among French adolescents (7-12th grades), one in 1993 (N=8435, 48.8% males), another in 1999 (N=11,331, 47.9% males). Increase in all substance use and polydrug use was observed (total sample, by gender and by age). The increase was important (1) for lifetime consumption of cannabis, "tobacco+cannabis," "alcohol+tobacco" and "alcohol+tobacco+cannabis" (OR=3.0); (2) for regular consumption of cannabis and "tobacco+cannabis" (OR=3.0); (3) among girls; (4) among youngsters aged 15 and more. In summary, these patterns of increase were quite different from those we expected for France, a wet and masculine culture.     

Sub-critical Column and Capillary Chromatography with Water as Mobile Phase and Flame Ionization Detection

A sub-critical chromatography (SubWC) with water as mobile phase and FID detection system is employed to separate several alcohols with high or medium polarity, with pure water as the eluent. The flow rate gets up to 50 μ1-min^-1 for packed column (1 mm i.d.) and 70 μ1-min^-1 for capillary (50 μm i.d.). Increasing the temperatureup to 140℃, together with temperature programming, markedly improves the separation and peak shapes within short analysis time. Sub-critical state is guaranteed.     

Synthesis of biphenyl derivatives as ACE and α-amylase inhibitors

Angiotensin converting enzyme (ACE) and α-amylase inhibitors were synthesized using 4′-(bromomethyl)-biphenyl-2-carbonitrile 1 and various cyclic secondary amines (a–h). The nitrile group appended to biphenyl was converted into tetrazole 3a–3h and the tetrazole was ring transformed into 1,3,4-oxadiazole derivatives 4a–4h. Some of the compounds have exhibited significant ACE and α-amylase inhibition.     

Inhibition of IL-1β and IL-6 in osteoblast-like cell by isoflavones extracted fromSophorae fructus

Osteoporosis is recognized as one of the major hormonal deficiency diseases, especially in menopausal women and the elderly. When estrogen is reduced in the body, local factors such as IL-1beta and IL-6, which are known to be related with bone resorption, are increased and promote osteoclastogenesis, which is responsible for bone resorption. In the present study, we investigated whether glucosidic isoflavones (Isocal, PIII) extracted from Sophorae fructus affect the proliferation of osteoblasts and prevent osteoclastogenesis in vitro by attenuating upstream cytokines such as IL-1beta and IL-6 in a human osteoblastic cell line (MG-63) and in a primary osteoblastic culture from SD rat femurs. Interestingly, IL-1beta and IL-6 mRNA were significantly suppressed in osteoblast-like cells treated with 17beta-estradiol (E2) and PIII when compared to positive control (SDB), and this suppression was more effective at 10(-8)% than at the highest concentration of 10(-4)%. In addition, these were confirmed in protein levels using ELISA assay. In the cell line, the cells showed that E2 was the most effective in osteoblastic proliferation over the whole range of concentration (10(-4)%-10(-12)%), even though PIII also showed the second greatest effectiveness at 10(-8)%. Nitric oxide (NO) was significantly (p<0.05) upregulated in PIII and E2 over the concentration range 10(-6)% to 10(-8)% when compared to SDB, without showing any dose dependency. In bone marrow primary culture, we found by TRAP assay that PIII effectively suppressed osteoclastogenesis next to E2 in comparison with SDB and culture media (control). In conclusion, these results suggest that local bone-resorbing cytokines can be regulated by PIII at lower concentrations and that, therefore, PIII may preferentially induce anti-osteoporosis response by attenuating osteoclastic differentiation and by upregulating NO.     

Plasma paraoxonase and arylesterase activities in smokers and smokeless tobacco users as Maraş powder

Abstract

Context: Mara? powder (MP), a different type of smokeless tobacco (ST) prepared from a tobacco called Nicotiana rustica Linn, is widely used in the Southern Turkey. Smoking and ST cause oxidative stress (OS) in the human body. Paraoxonase (PON) and arylesterase (ARE) are antioxidant enzymes.

Objective: To investigate the effects of MP on activities of PON, ARE, and malondialdehyde (MDA) levels in plasma and to compare these parameters in smokers and MP users (MPU).

Materials and methods: The study consisted of smokers, MPU, and control group (CG) neither smoking nor using MP healthy subjects. PON and ARE activities were measured spectrophotometrically using paraoxon and phenylacetate substrates, respectively.

Results: PON and ARE activities were decreased whereas MDA levels were increased in tobacco groups compared to the CG. The differences of ARE and MDA values between the tobacco groups and CG were found statistically significant (p?<?0.01). But no significant differences were detected between the groups in the activity of PON (p?>?0.05). However, the lowest activities of the enzymes were obtained in MPU.

Conclusion: Our results can help to evaluate harmful effects of cigarette and ST as MP. These effects can be attributed to increased OS. Increased plasma MDA levels and decreased ARE activities may be important in assessing oxidant/antioxidant imbalance in MPU as well as smokers. Also, using of MP has harmful effects at least cigarette smoking.     

Meta-analyses of occupational exposure as a painter and lung and bladder cancer morbidity and mortality 1950–2008

The International Agency for Research on Cancer (IARC) classified occupational painting as a human carcinogen based on lung and bladder cancers; however, no specific exposures were implicated. The authors conducted comprehensive meta-analyses of the epidemiological literature on occupational painting and these cancers. The authors abstracted study results and confounder information, and used quantile plots and regression models to evaluate heterogeneity and publication bias. Summary risk estimates were derived and sensitivity analyses performed to evaluate smoking, socioeconomic status (SES), and exposure variables. Where applicable, a Bayesian approach was used to externally adjust for smoking, a major risk factor for both cancers. For lung cancer cohort mortality studies, publication bias and heterogeneity were seen, and earlier studies reported higher risk estimates than later studies. Overall lung cancer summary risk estimates were 1.29 for case-control and 1.22 and 1.36 for cohort morbidity and mortality studies, respectively, and risk estimates for bladder cancer were 1.28 for case-control and 1.14 and 1.27 for cohort morbidity and mortality studies, respectively (all statistically significant). Risks did not differ between painters and mixed occupations. Nonsignificant summary estimates resulted for lung and bladder cancers when controlling for SES, or externally adjusting for smoking in lung cancer studies. Summary risks varied by control source for case-control studies. Residual confounding by smoking and SES, lack of exposure group effect, and publication bias limit the ability of the meta-analyses to explain associations observed between occupational painting and lung and bladder cancers. Given the long latencies for lung and bladder cancers, these weak associations, if real, may not be elucidated through studies of occupational painting today.     

Interleukin-1β-converting enzyme and related proteases as potential targets in inflammation and apoptosis

Summary Interleukin-1-converting enzyme (ICE, EC 3.4.22.36) is the cysteine protease responsible for the production of interleukin-1 in monocytes. Since its discovery in 1989, this enzyme has been the subject of enthusiastic investigation because of the suspected role of this cytokine in the pathogenesis of inflammatory diseases such as rheumatoid arthritis. These studies have culminated in the purification and cloning of the enzyme, development of potent inhibitors, determination of its structure by X-ray crystallography and the development of knockout mice, which have confirmed an important role for this protease in inflammation. Late in 1993, the protease became the subject of further interest because of its homology to CED-3, the product of a gene required for programmed cell death in the nematodeC. elegans. It is now clear that ICE is the first identified member of a new cysteine protease family that includes CED-3 and at least four other human homologues. Although the extent to which ICE itself plays a role in mammalian apoptosis remains controversial, it is clear that at least one of these homologues, CPP32, is an important player. The recognition that members of this family play key biological roles in both inflammation and apoptosis, two extremely attractive targets for therapeutic intervention, has led to intense interest in these proteases.     

Paeoniflorin improves survival in LPS-challenged mice through the suppression of TNF-α and IL-1β release and augmentation of IL-10 production

Lipopolysaccharide (LPS) plays an important role in Gram-negative bacteria-induced sepsis and multiple organ dysfunction syndrome, which are still the leading cause of high mortality in intensive care units. Although paeoniflorin (Pae) has reportedly exhibited anti-inflammatory effect and protection against immunological liver injury in mice, it is not known whether Pae improve survival in endotoxemic mice. The purpose of this study was to determine the effect of Pae on the mortality, multiple organ dysfunction and cytokine production in lipopolysaccharide (LPS)-treated mice. We found that pretreatment with Pae decreased mortality, reduced lung and kidney injury, decreased serum creatinine level and improve systolic function of heart in mice challenged with LPS. Further experiments showed that Pae inhibited LPS-stimulated tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) release and promoted LPS-induced interleukin-10 (IL-10) production. Our results indicate that Pae protects mice against lethal LPS challenge, at least in part, through inhibiting TNF-α and IL-1β production and accelerating IL-10 expression.     

Preparation of aromatic β-Selenolactams and their bioactivities as agricultural chemicals

The purpose of this study was to investigate the possibility of aromatic beta-selenolactams being used in agricultural chemicals. A series of beta-selenolactams with aromatic substituents at the 1-, 2- and 3-positions were synthesized and their bioactivities were evaluated. Acarianicidal and insecticidal activity against common destructive insects, antibacterial activity against seven common plant pathogens, and plant growth activity of typical food crops were investigated. We found that introduction of 4-chloro and 4-methyl groups on 2- or 3-phenyl groups of the beta-selenolactam ring brought about acarianicidal activity against adults and eggs of Plutella xylostella. However, except for moderate to weak effect on fatality of Culex pipiens molestus Forskal, insecticidal activity against two other kinds of insects, antibacterial activity against plant pathogens, and activity on plant growth regulation were not detected among the beta-selenolactam derivatives.     

Design and synthesis of 3′-fluoropenciclovir analogues as antiviral agents

Based on fluorine switch approach, a series of 3′-fluoropenciclovir analogues with different purine and pyrimidine bases were designed and synthesized. Direct reduction of β-fluoroester to the corresponding 3-fluoroalcohol provided an easy and new entry pathway towards the synthesis of 3′-fluoropenciclovir analogues. The synthesized 3′-fluoropenciclovir analogues were evaluated for their antiviral activities against the poliovirus, HSV-1, HSV-2 and HIV.     

The Discovery of Pyridone and Pyridazone Heterocycles as γ-Secretase Modulators

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