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In-vitro
Terms modified by In-vitro Selected AbstractsAstaxanthin, a dietary carotenoid, protects retinal cells against oxidative stress in-vitro and in mice in-vivoJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2008Yoshimi Nakajima We have investigated whether astaxanthin exerted neuroprotective effects in retinal ganglion cells in-vitro and in-vivo. In-vitro, retinal damage was induced by 24-h hydrogen peroxide (H2O2) exposure or serum deprivation, and cell viability was measured using a WST assay. In cultured retinal ganglion cells (RGC-5, a rat ganglion cell-line transformed using E1A virus), astaxanthin inhibited the neurotoxicity induced by H2O2 or serum deprivation, and reduced the intracellular oxidation induced by various reactive oxygen species (ROS). Furthermore, astaxanthin decreased the radical generation induced by serum deprivation in RGC-5. In mice in-vivo, astaxanthin (100 mg kg,1, p.o., four times) reduced the retinal damage (a decrease in retinal ganglion cells and in thickness of inner plexiform layer) induced by intravitreal N -methyl- d -aspartate (NMDA) injection. Furthermore, astaxanthin reduced the expressions of 4-hydroxy-2-nonenal (4-HNE)-modified protein (indicator of lipid peroxidation) and 8-hydroxy-deoxyguanosine (8-OHdG; indicator of oxidative DNA damage). These findings indicated that astaxanthin had neuroprotective effects against retinal damage in-vitro and in-vivo, and that its protective effects may have been partly mediated via its antioxidant effects. [source] In-vitro and in-vivo characterization of a buprenorphine delivery systemJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2006Sofie R. Kleppner Buprenorphine is a mu-opioid receptor partial agonist with enhanced safety and comparable efficacy to methadone for treatment of opioid dependence. The sublingual formulation of buprenorphine, approved for treatment of opioid dependence, produces variable buprenorphine blood levels and requires frequent dosing that limits patient compliance. To achieve stable buprenorphine levels that may improve patient outcome, an implantable sustained buprenorphine delivery system was developed. Each implant consists of ethylene vinyl acetate copolymer and 90 mg buprenorphine HCl, and measures 26 mm in length and 2.4 mm in diameter. Steady-state release in-vitro was 0.5 mg/implant/day. In-vivo pharmacokinetics and safety were examined for up to 52 weeks in beagle dogs receiving 8, 16 or 24 subcutaneous implants. Plasma buprenorphine concentrations correlated with the number of implants administered. Peak buprenorphine concentrations were generally reached within 24 h after implantation. Steady-state plasma levels were attained between 3 and 8 weeks, and were maintained for study duration, with a calculated mean release rate of 0.14 ± 0.04 mg/implant/day. There were no test-article-related adverse effects. This delivery system can provide long-term stable systemic buprenorphine levels, and may increase patient compliance, thereby improving outcome for opioid-dependent patients. [source] In-vitro and in-vivo assays for angiogenesis-modulating drug discovery and developmentJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2006Michelle W. Phung In the past 35 years, significant findings have been made in relation to angiogenesis, and how this usually normal physiological function is converted into an abnormal state in cancer. To search for agents that can inhibit angiogenesis, and thereby prevent a tumour from proliferation and spread that is ultimately fatal to the patient, various in-vitro assays have been developed. In addition, older assays have been refined usually into high throughput screening formats, mainly by the biopharmaceutical industry in their attempts to develop novel therapeutic molecules and maintain a pipeline of lead candidates. The central aim is to extract more accurate data that would facilitate the birth of innovative mechanisms to defeat aberrant angiogenesis in-vivo. At the same time, better in-vivo models have been established, with the goal to mimic as close as possible the natural progression of various types of neoplasms in response to a good angiogenic response. More clinically relevant models are needed as anti-angiogenesis drug discovery and drug development companies fast track their lead molecules from preclinical investigations to phase I clinical trials. [source] Statins and osteoporosis: new role for old drugsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2006Satyawan B. Jadhav Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditure. Most of the current therapies available for its treatment are limited to the prevention or slowing down of bone loss rather than enhancing bone formation. Recent discovery of statins (HMG-CoA reductase inhibitors) as bone anabolic agents has spurred a great deal of interest among both basic and clinical bone researchers. In-vitro and some animal studies suggest that statins increase the bone mass by enhancing bone morphogenetic protein-2 (BMP-2)-mediated osteoblast expression. Although a limited number of case,control studies suggest that statins may have the potential to reduce the risk of fractures by increasing bone formation, other studies have failed to show a benefit in fracture reduction. Randomized, controlled clinical trials are needed to resolve this conflict. One possible reason for the discrepancy in the results of preclinical, as well as clinical, studies is the liver-specific nature of statins. Considering their high liver specificity and low oral bioavailability, distribution of statins to the bone microenvironment in optimum concentration is questionable. To unravel their exact mechanism and confirm beneficial action on bone, statins should reach the bone microenvironment in optimum concentration. Dose optimization and use of novel controlled drug delivery systems may help in increasing the bioavailability and distribution of statins to the bone microenvironment. Discovery of bone-specific statins or their bone-targeted delivery offers great potential in the treatment of osteoporosis. In this review, we have summarized various preclinical and clinical studies of statins and their action on bone. We have also discussed the possible mechanism of action of statins on bone. Finally, the role of drug delivery systems in confirming and assessing the actual potential of statins as anti-osteoporotic agents is highlighted. [source] In-vitro and in-vivo anti-allergic actions of Arecae semenJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2004Jun Ho Lee The effects of various extracts from oriental medicinal herbs on mast cell-mediated allergic reactions have been investigated. Among the extracts, Arecae semen was the most potent inhibitor of antigen-induced degranulation in RBL-2H3 mast cells. A. semen inhibited DNP-BSA- and compound 48/80-induced degranulation in RBL-2H3 mast cells with IC50 values of approximately 53 and 52 ,g mL,1, respectively, and inhibited compound 48/80-induced systemic anaphylaxis by 46% at 300 mg kg,1 in mice. A. semen also inhibited the expression of TNF-, and the activation of mitogen activated protein kinase, ERK1/2, which is critical for the production of inflammatory cytokines in mast cells, as indicated by the suppression of the activating phosphorylation of ERK1/2. These results suggest that A. semen may be useful for the treatment of various immediate and delayed allergic diseases. [source] In-vitro and in-vivo studies of cefpirom using bile salts as absorption enhancersJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2003Yahya Mrestani ABSTRACT Cephalosporins have to be administered by injection because of the poor intestinal absorption of the orally delivered drugs. Because of the obvious drawbacks of drug delivery by injection, the development of alternatives with enhanced oral bioavailability is receiving much attention in pharmaceutical research. Cefpirom (Cp) is a new semi-synthetic amino-2-thiazolyl-methoxyimino cephalosporin that has been substituted in position 3 with a cyclopenteno-pyridinium group in order to create a zwitterionic compound. It exhibits highly hydrophilic properties, as shown from its extremely low partition coefficient, and therefore its lipophilicity was increased using bile salts. The effect of this on the partition coefficients determined in the n-octanol/buffer system was confirmed using an in-vitro transport model with artificial and biological membranes. The pharmacokinetic properties of Cp were investigated in rabbits after intraduodenal administration with and without bile salts. Furthermore, the physiological compatibility of the bile salts was investigated using active D-glucose transport. [source] In-vitro and in-vivo antioxidant activity of different extracts of the leaves of Clerodendron colebrookianum Walp in the ratJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2003D. Rajlakshmi ABSTRACT The in-vitro antioxidant activities of different concentrations of the water, alcoholic, petroleum ether and ethyl acetate extracts of the dried leaves of Clerodendron colebrookianum Walp, and in-vivo antioxidant activity of the water extract was studied in experimental rat models. The results obtained from in-vitro lipid peroxidation induced by FeSO4 -ascorbate in rat liver homogenate showed a significant inhibition of lipid peroxidation by different extracts of C. colebrookianum leaf. Water extracts at concentrations (w/v) of 1:30, 1:50, 1:200 and 1:1000 showed the strongest inhibitory activity over the other organic extracts, suggesting maximum antioxidant effect. Chronic feeding of the water extract to Wistar albino rats (both sexes, 150,200g) in 1 or 2g kg,1/day doses for 14 days significantly increased the ferric reducing ability of plasma by 19% and 40% on the seventh day, and by 45% and 57% on the fourteenth day of treatment, respectively. Thiobarbituric acid reactive substances (TBARS), as a marker of lipid peroxidation, and some cellular antioxidants (superoxide dismutase, catalase and reduced glutathione) were estimated in heart, liver and kidney. There was a significant reduction in hepatic and renal TBARS with both the doses, without any change in myocardial TBARS. There was no change in the level of antioxidants in heart, liver and kidney, except for the hepatic superoxide dismutase. The findings of this study showed that the leaf extract of C. colebrookianum increased the antioxidant capacity of blood and had an inhibitory effect on the basal level of lipid peroxidation of liver and kidney. This lends scientific support to the therapeutic use of the plant leaves, as claimed by the tribal medicine of North-East India. [source] Curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitroJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2002Hee-Chul Kang We previously demonstrated that curcumin, a well-known antioxidant, inhibits collagen deposition in carbon tetrachloride-induced liver injury in rats. The major effector cells responsible for collagen synthesis in the liver are activated hepatic stellate cells. In this study, we investigated the inhibitory effects of curcumin on the collagen synthesis and activation of rat hepatic stellate cells in-vitro, and on hepatic stellate cell activation in-vivo. The effects of curcumin on the production of collagen and smooth muscle ,-actin proteins and of ,1(I) collagen mRNA were studied in-vivo and in-vitro. The effect of curcumin on DNA synthesis was also determined in-vitro. In-vivo, treatment with curcumin reduced collagen deposition and smooth muscle ,-actin-positive areas and lowered mRNA levels of type I collagen in the liver. In-vitro, curcumin at a concentration of 5 ,g mL,1 reduced DNA synthesis, and downregulated smooth muscle ,-actin and type I collagen expression, and ,1(I) collagen mRNA expression. We concluded that curcumin inhibits collagen synthesis and hepatic stellate cell activation in-vivo and in-vitro, and thus may prove a valuable anti-fibrogenic agent. [source] In-vitro and in-vivo immunomodulatory effects of syringinJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2001Jae Youl Cho Syringin was found to possess immunomodulatory activity by which it inhibited the in-vitro immunohaemolysis of antibody-coated sheep erythrocytes by guinea-pig serum through suppression of C3-convertase of the classical complement. In this study, we examined its in-vitro and in-vivo activity on tumour necrosis factor (TNF)-, and nitric oxide (NO) production, CD4 + T cell and CD8+ cytotoxic T cell (CTLL-2) proliferation, and croton oil-, arachidonic acid- and fluorescein-isothiocynate (FITC)-induced mouse ear oedema model. Syringin significantly inhibited both TNF-, production from lipopolysaccharide (LPS)-stimulated RAW264.7 cells and CD8+ T cell (CTLL-2) proliferation in a dose-dependent manner, whereas neither NO production nor CD4+ T cell proliferation were blocked even by high concentrations of syringin. In the in-vivo experiments, syringin also significantly suppressed FITC-induced ear oedema in mice but not the ear oedema induced by croton or arachidonic acid. These results suggest that syringin may be implicated as an immunomodulator having an anti-allergic effect rather than an antiinflammatory effect. The anti-allergic effect of syringin seems to be due, in part, to inhibition of TNF-, production and cytotoxic T cell proliferation. [source] In-vitro and in-vivo evaluation of pH-responsive polymeric micelles in a photodynamic cancer therapy modelJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2001J. Taillefer pH-sensitive polymeric micelles of randomly and terminally alkylated N-isopropylacrylamide copolymers were prepared and characterized. Aluminium chloride phthalocyanine (AlClPc), a second generation sensitizer for the photodynamic therapy of cancer, was incorporated in the micelles by dialysis. Their photodynamic activities were evaluated in-vitro against EMT-6 mouse mammary tumour cells and in-vivo against EMT-6 tumours implanted intradermally on each hind thigh of Balb/c mice. pH-sensitive polymeric micelles were found to exhibit greater cytotoxicity in-vitro than control Cremophor EL formulations. In the presence of chloroquine, a weak base that raises the internal pH of acidic organelles, in-vitro experiments demonstrated the importance of endosomal/lysosomal acidity for the pH-sensitive polymeric micelles to be fully effective. Biodistribution was assessed by fluorescence of tissue extracts after intravenous injection of 2 ,mol kg,1 AlClPc. The results revealed accumulation of AlClPc polymeric micelles in the liver, spleen and lungs, with a lower tumour uptake than AlClPc Cremophor EL formulations. However, polymeric micelles exhibited similar activity in-vivo to the control Cremophor EL formulations, demonstrating the higher potency of AlClPc polymeric micelles when localized in tumour tissue. It was concluded that polymeric micelles represent a good alternative to Cremophor EL preparations for the vectorization of hydrophobic drugs. [source] Reduction of the Potential Anticancer Drug Oracin in the Rat Liver In-vitroJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2000BARBORA SZOTÁKOVÁ Studies on the metabolism of the potential cytostatic drug oracin have shown that a principal metabolite of oracin is 11-dihydrooracin (DHO). We conducted in-vitro experiments to investigate the extent of oracin carbonyl reduction in microsomal or cytosolic fractions and to find out the enzymes involved under these conditions. Among several inducers of rat cytochrome P450 only 3-methylcholanthrene caused a significant (P < 0.01) stimulation (1.9 times) of DHO production in microsomal fraction and the specific P4501A inhibitor ,-naphthoflavone significantly (P < 0.01) decreased (twice) the induced reduction activity. Cytochrome P4501A participates in oracin reduction in microsomes. 18,-Glycyrrhetinic acid, a specific inhibitor of hydroxysteroid dehydrogenase, significantly (P < 0.01) inhibited the production of DHO in the microsomal fraction (>95% inhibition) in comparison with the non-inhibited reaction. Statistically significant (P < 0.01) inhibition (95%) of DHO formation was caused by metyrapone, which is also the substrate of 11,-hydroxysteroid dehydrogenase. The main microsomal enzyme which catalyses the carbonyl reduction of oracin is probably 11,-hydroxysteroid dehydrogenase. Important oracin reduction to DHO in the cytosolic fraction was found. According to its specific sensitivity towards quercitrin (inhibition by 99%, P < 0.01), the enzyme responsible for DHO formation in the rat liver cytosol is postulated to be carbonyl reductase. [source] Characterization of Histamine Release Induced by Fluoroquinolone Antibacterial Agents In-vivo and In-vitroJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 5 2000KAZUHIKO MORI Characterization of histamine release induced by fluoroquinolone antibacterial agents, levofloxacin and ciprofloxacin, was investigated in-vivo and in-vitro. Intravenous injection of levofloxacin and ciprofloxacin at 1,10 mg kg,1 produced dose-related elevations in plasma histamine level in anaesthetized dogs. In contrast, levofloxacin was devoid of plasma histamine increment in anaesthetized rats at 100 mg kg,1, whereas ciprofloxacin at the same dose caused endogenous histamine release. Levofloxacin and ciprofloxacin induced non-cytotoxic secretion of histamine from all mast cells tested in a concentration-dependent manner, whereas rat skin and peritoneal mast cells were thirty- to one-hundred-times less sensitive to the effect of fluoroquinolones as compared with the canine skin mast cells. These results suggest that the functional heterogeneity of mast cells from different species in histamine releasing activity of fluoroquinolones may exist, and that mast cells from the dog appear to be particularly sensitive to the effect of the fluoroquinolones. [source] Controlled Transdermal Delivery of Propranolol Using HPMC Matrices: Design and In-vitro and In-vivo EvaluationJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2000P. R. P. VERMA To improve bioavailability and achieve a smoother plasma-concentration profile as compared with oral administration, a matrix-dispersion-type transdermal delivery system was designed and developed for propranolol using different ratios of hydroxypropyl-methylcellulose (HPMC) K4M, K15M and K100M. Formulations were evaluated for in-vitro dissolution characteristics using a Cygnus' sandwich-patch holder. Drug release followed Higuchi rather than zero-order or first-order kinetics. In-vivo evaluation was carried out on healthy volunteers (21 ± 1.41 years; 60.89 ± 5.35 kg) following the balanced incomplete block design. The dissolution rate constant (k) and data generated from plasma and urine (Cmax, maximum plasma concentration; tmax, time to reach peak plasma concentration; AUC, area under the curve; ke, elimination rate constant; t½e, elimination half-life; ka, absorption rate constant; t½a, absorption half-life) were evaluated statistically by two-way analysis of variance. Statistically excellent correlation was found between the percentage of drug absorbed and Cmax, AUC0,24 and AUC0-,. A highly significant difference (P < 0.001) was observed when Cmax and AUC0-, generated from plasma and urine were compared, but ke, t½e, ka and t½a did not differ significantly (P > 0.1). We conclude that urinary excretion data may be used as a simpler alternative to blood level data in studying the kinetics of absorption and deriving the absorption parameters. [source] Textilien mit antimykotischen und antibakteriellen EigenschaftenMYCOSES, Issue 2008U. C. Hipler Zusammenfassung Auf der Basis des ZIMMER Lyocell Verfahrens erfolgt die Herstellung von SeaCell® und SeaCell® Active Fasern. Eine besondere Fähigkeit der SeaCell® Faser ist, Stoffe zu binden und zu absorbieren. Die spezielle Fähigkeit der Metallsorption wird bei der Aktivierung von SeaCell® Fasern ausgenutzt. Dabei kann das bakterizid wirkende Metall Silber vom bereits fertig ausgeformten cellulosischen Faserkörper absorbiert werden. Die vorliegende Studie zeigt die antimykotische Wirkung von SeaCell®Active in einem In-vitro -Testsystem gegenüber Candida albicans (DSM 11225), Candida tropicalis (ATCC 1169) und Candida krusei (ATCC 6258). Darüber hinaus wurde die antibakterielle Aktivität der Fasern mit unterschiedlichen Mengen an SeaCell® Active dosisabhängig gegenüber Staphylococcus aureus (ATCC 22923) und Escherichia coli (ATCC 35218) nachgewiesen. Ob diese Faser in bioaktiven Textilien Verwendung finden kann, die für spezifische anatomische Regionen und Hautbedingungen mit einer Suszeptibilität für Pilz-und Bakterieninfektionen, speziell Candida -Spezies, Staphylococcus aureus und Escherichia coli geeignet ist, muss durch weitere Untersuchungen, insbesondere in-vivo -Tests am Menschen, unter Berücksichtigung möglicher allergischer und toxischer Effekte der Fasern, sichergestellt werden. Summary SeaCell® and SeaCell® Active fibers can be produced on the basis of the ZIMMER Lyocell process. One particularity of the SeaCell® fiber is its capacity to bind and absorb substances. During the activation of SeaCell® fibers the bactericidal metal silver is absorbed by the fully formed cellulosic fiber through metalsorption. The present study demonstrates the antifungal and antibacterial effect of SeaCell®Active in an in vitro test system against Candida albicans (DSM 11225), Candida tropicalis (ATCC 1169) and Candida krusei (ATCC 6258). Furthermore, the antibacterial activity of fibers with different amounts of SeaCell® Active fibers in a dose-dependent manner against Staphylococcus aureus (ATCC 22923) and Escherichia coli (ATCC 35218) could be demonstrated. If this fiber seems to be suited for bio-active textiles in specific anatomical body regions and skin conditions with a susceptibility for fungal and bacterial infections namely with Candida species, Staphylococcus aureus and Escherichia coli must be examined by means of further investigations, especially in vivo tests in human considering allergic and toxic effects of the fiber. [source] Vaccination against the Old World screwworm fly (Chrysomya bezziana)PARASITE IMMUNOLOGY, Issue 11 2000Sukarsih Chrysomya bezziana is an endemic pest of livestock or a threat to livestock production in large areas of Africa, the Middle East, southern and south-east Asia and Australia. Its control is difficult. The feasibility of vaccinating against this pest has now been explored. In-vitro and in-vivo assays have been established. Using these assays, it has been shown that first instar larvae, third instar peritrophic membrane and cardia are all sources of material able to induce immunological reactions in sheep which lead to significant reductions in larval growth. In-vitro assays following vaccination with peritrophic membrane also show larval mortality. Taken together, these effects lead to an 82% reduction in the weight of recovered larvae in vitro and 45% reduction in vivo. Preliminary evidence suggests that the mechanism of protection may be complex. [source] In-vitro and in-vivo evidence of dose-dependent decrease of uropathogenic Escherichia coli virulence after consumption of commercial Vaccinium macrocarpon (cranberry) capsulesCLINICAL MICROBIOLOGY AND INFECTION, Issue 4 2008J.-P. Lavigne Abstract This study evaluated the antibacterial efficacy of the consumption of cranberry capsules vs. placebo in the urine of healthy volunteers. A first double-blind, randomised, crossover trial involved eight volunteers who had followed three regimens, with or without cranberry, with a wash-out period of at least 6 days between each regimen. Twelve hours after consumption of cranberry or placebo hard capsules, the first urine of the morning was collected. Different Escherichia coli strains were cultured in the urine samples. Urinary antibacterial adhesion activity was measured in vitro using the human T24 epithelial cell-line, and in vivo using the Caenorhabditis elegans killing model. With the in-vitro model, 108 mg of cranberry induced a significant reduction in bacterial adherence to T24 cells as compared with placebo (p <0.001). A significant dose-dependent decrease in bacterial adherence in vitro was noted after the consumption of 108 and 36 mg of cranberry (p <0.001). The in-vivo model confirmed that E. coli strains had a reduced ability to kill C. elegans after growth in the urine of patients who consumed cranberry capsules. Overall, these in-vivo and in-vitro studies suggested that consumption of cranberry juice represents an interesting new strategy to prevent recurrent urinary tract infection. [source] Tolerogenic dendritic cells pulsed with enterobacterial extract suppress development of colitis in the severe combined immunodeficiency transfer modelIMMUNOLOGY, Issue 4 2007A. E. Pedersen Summary Immunomodulatory dendritic cells (DCs) that induce antigen-specific T-cell tolerance upon in vivo adoptive transfer are promising candidates for immunotherapy of autoimmune diseases. The feasibility of such a strategy has recently proved its efficacy in animal models of allotransplantation and experimental allergic encephalitis, but the effect in inflammatory bowel disease has not yet been demonstrated. In severe combined immunodeficient (SCID) mice, adoptively transferred CD4+ CD25, T cells repopulate the lymphoid tissues and lead to development of chronic colitis characterized by CD4+ T-cell proliferation against enterobacterial extract in vitro. In this model, we adoptively transferred in-vitro -generated bone-marrow-derived DCs exposed to interleukin-10 (IL-10) and an enterobacterial extract. We show that these cells are CD11c positive with intermediate expression of CD40, CD80 and CD86 and have a diminished secretion of IL-6, IL-12 p40/70, tumour necrosis factor-, and keratinocyte-derived chemokine (KC) compared to DCs treated with enterobacterial extract alone. In vivo, these cells prevented weight loss in SCID mice adoptively transferred with CD4+ CD25, T cells, resulted in a lower histopathology colitis score and tended to result in higher serum levels of IL-1,, IL-10, IL-12, IL-13, IL-17, KC and monokine induced by interferon-gamma (MIG). These data underscore the potential of using immunomodulatory DCs to control inflammatory bowel disease and demonstrate its potential use in future human therapeutic settings. [source] Role of topical and nutritional supplement to modify the oxidative stress,INTERNATIONAL JOURNAL OF COSMETIC SCIENCE, Issue 6 2002P. Morganti Synopsis Background: Evidence suggests that signs of skin ageing such as wrinkling, ragging and actinic lentigines, may be connected to cumulative oxidative damage incurred throughout our lifetimes. To counteract this oxidative injury, skin is equipped with a network on enzymatic and non-enzymatic antioxidant systems, such as tocopherols, ascorbate polyphenols. All these compounds administered topically by cosmetics or by oral route by diet supplements, have been shown to exert an antioxidant/protective effect in skin or skin cells. Objective: The object of this study was to evaluate both in vitro and in vivo the activity performed by different topical antioxidants and nutritional supplements. Methods: A randomized double-blind placebo-controlled study was carried out for 8 weeks on 30 dry-skinned elderly volunteers, women aged between 48 and 59 years, with moderate xerosis and photoageing. Surface skin lipids, skin hydration and MDA determination were topically detected by 3C System. ROS was evaluated on the blood serum and on IL-3 stimulated human leukocytes by ROS Meter System at 505 nm. All the subjects applied twice a day for 2 months a nanocolloidal gel and/or take a diet supplement by oral route at the quantity of two capsules per day. All the formulations used were antioxidant-enriched (ascorbic acid, tocopherol, alpha-lipoic acid, melatonin, emblica). Results: Oxidative stress and consequently lipids peroxidation decreased from 30 to 40% (P < 0.005) in blood serum of all the subjects treated with antioxidant compounds topically and by oral route. Both free radicals recovered in blood serum and on skin (in vivo) and ROS induced by irradiation of leucocytes with UVB light (in vitro), appear sensibly lower in subjects antioxidant-treated. Conclusions: From the obtained data, it seems possible to conclude that all the compounds used play interesting role as topical and systemic photoprotectants, thanks to their interesting antioxidant property. Moreover, the antioxidant treatment seems to be a promising therapeutic approach also in reducing the oxidative stress of people affected by photoaging. Résumé Les faits semblent montrer que les signes du vieillissement cutané tels que les rides, la perte d'élasticité ou les taches de vieillesse, peuvent être liés aux effets oxydants cumulés subis tout au long de la vie. Pour contrer ces effets oxydants, la peau est équipée d'un réseau de systèmes antioxydants enzymatiques et non enzymatiques tels que les tocophérols, l'ascorbate et les polyphénols. Tous ces composés, administrés par voie topique par des cosmétiques ou par voie orale avec des suppléments alimentaires, se sont révélés exercer un effet antioxydant/protecteur sur la peau ou les cellules de la peau. L'objet de cette étude était d'évaluer aussi bien in-vitro qu'in-vivo l'activité de différents antioxydants topiques et suppléments alimentaires. Une étude randomisée contre placebo en double aveugle a été conduite sur 8 semaines avec 30 volontaires,gés à peau sèche, des femmes de 48 à 59 ans, présentant une xérose et un viellissement modéré. Les lipides à la surface de la peau, l'hydratation de la peau et la MDA ont été suivis de façon topique par le SYSTEM 3 C. Les ROS (Reactive Oxygen Species) ont été déterminés dans le sérum sanguin et sur les leucocytes humains 12-3 stimulés par un SYSTEM ROS-METER à 505 nm. Tous les sujets ont appliqué deux fois par jour pendant deux mois un gel nanocolloïdal et/ou pris des suppléments alimentaires par voie orale à raison de deux gélules par jour. Toutes les formulations utilisées étaient enrichies en antioxydant (acide ascorbique, tocophérol, acide alpha-lipoïque, mélatonine, emblica). Le stress oxydant et par conséquent la péroxydation des lipides diminue de 30 à 40% (p < 0.005) dans le sérum sanguin de tous les sujets traités avec des composés antioxydants par voie topique ou orale. Les radicaux libres retrouvés aussi bien dans le sérum sanguin que dans la peau (in-vivo) et la ROS induite par l'irradiation des leucocytes avec la lumière ultraviolette (in-vitro) apparaissent significativement moins élevés chez les sujets traités aux antioxydants par voie topique ou orale. D'après les données obtenues il semble possible de conclure que tous les composés utilisés jouent un rôle intéressant comme photoprotecteurs topiques et systémiques grâce à leurs intéressantes propriétés antioxydantes. De plus, le traitement antioxydant semble être une approche thérapeutique prometteuse en ce qu'elle réduit aussi le stress oxydant des personnes touchées par le vieillissement. [source] Chronic myelogenous leukaemia , new therapeutic principlesJOURNAL OF INTERNAL MEDICINE, Issue 1 2001Michael E. O'Dwyer O'Dwyer ME, Druker BJ (Oregon Health Sciences University, Portland, USA). Chronic myelogenous leukaemia , new therapeutic principles. J. Intern Med 2001; 250: 3,9 The deregulated tyrosine kinase activity of the BCR-ABL fusion protein is the cause of malignant transformation in almost all cases of chronic myelogenous leukaemia (CML), making BCR-ABL an ideal target for pharmacological inhibition. Signal transduction inhibitor (STI571) (formerly CGP57 148B), is an ABL specific, tyrosine kinase inhibitor. In preclinical studies, it has been shown to selectively kill BCR-ABL expressing cells, both in-vitro and in vivo. The results of clinical studies to date are highly encourageing and STI571 promises to be an important addition to the therapy of CML. [source] A bioassay for mosquito repellency against Aedes aegypti: method validation and bioactivities of DEET analoguesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2010Alexander Jahn Abstract Objectives Vector-borne diseases are still a major mortality factor in Africa and South-east Asia and effective mosquito repellents are therefore needed. An efficient and safe in-vitro assay system using artificial blood and skin substitute could facilitate the development of novel repellents, as most assays currently rely on human subjects or vertebrate whole blood. Moreover, examining the skin permeation profiles could provide safer mosquito repellents. The new assay system could serve as an initial system for testing new repellent candidates upon validation with DEET and its analogues. MethodsN,N -Diethyl- meta -toluamide (DEET) and five analogues were synthesised and used to validate a novel in-vitro bioassay using artificial blood and collagen membrane. Repellency against Aedes aegypti was correlated with lipophilicity and skin permeation. Key findings The new in-vitro assay showed good reproducibility (interday relative standard deviation <10% at high concentrations). Four of the five DEET analogues showed repellency similar or superior to that of DEET. Repellency correlated linearly with lipophilicity but stronger repellents tended to permeate skin better. Conclusions The new in-vitro assay using blood substitute and collagen membrane significantly simplifies screening of possible mosquito repellents. Lipophilicity as well as skin permeation profiles should be considered before testing of compounds that are candidates for mosquito repellents. [source] Cyamemazine metabolites: effects on human cardiac ion channels in-vitro and on the QTc interval in guinea pigsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2008William Crumb Monodesmethyl cyamemazine and cyamemazine sulfoxide, the two main metabolites of the antipsychotic and anxiolytic phenothiazine cyamemazine, were investigated for their effects on the human ether-à-go-go related gene (hERG) channel expressed in HEK 293 cells and on native INa, ICa, Ito, Isus or IK1 of human atrial myocytes. Additionally, cyamemazine metabolites were compared with terfenadine for their effects on the QT interval in anaesthetized guinea pigs. Monodesmethyl cyamemazine and cyamemazine sulfoxide reduced hERG current amplitude, with IC50 values of 0.70 and 1.53 ,M, respectively. By contrast, at a concentration of 1 ,M, cyamemazine metabolites failed to significantly affect INa, Ito, Isus or IK1 current amplitudes. Cyamemazine sulfoxide had no effect on ICa at 1 ,M, while at this concentration, monodesmethyl cyamemazine only slightly (17%), albeit significantly, inhibited ICa current. Finally, cyamemazine metabolites (5 mg kg,1 i.v.) were unable to significantly prolong QTc values in the guinea pig. Conversely, terfenadine (5 mg kg,1 i.v.) significantly increased QTc values. In conclusion, cyamemazine metabolite concentrations required to inhibit hERG current substantially exceed those necessary to achieve therapeutic activity of the parent compound in humans. Moreover, cyamemazine metabolites, in contrast to terfenadine, do not delay cardiac repolarization in the anaesthetized guinea pig. These non-clinical findings explain the excellent cardiac safety records of cyamemazine during its 30 years of extensive therapeutic use. [source] Pharmacological profile of essential oils derived from Lavandula angustifolia and Melissa officinalis with anti-agitation properties: focus on ligand-gated channelsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2008Liping Huang Both Melissa officinalis (Mo) and Lavandula angustifolia (La) essential oils have putative anti-agitation properties in humans, indicating common components with a depressant action in the central nervous system. A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically validated essential oil derived from La, which has shown clinical benefit in treating agitation. La inhibited [35S] TBPS binding to the rat forebrain gamma aminobutyric acid (GABA)A receptor channel (apparent IC50 = 0.040 ± 0.001 mg mL,1), but had no effect on N -methyl- d -aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or nicotinic acetylcholine receptors. A 50:50 mixture of Mo and La essential oils inhibited [3H] flunitrazepam binding, whereas the individual oils had no significant effect. Electrophysiological analyses with rat cortical primary cultures demonstrated that La reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01,1 mg mL,1), whereas no inhibition of NMDA- or AMPA-induced currents was noted. La elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classic GABAA antagonist picrotoxin which evoked profound epileptiform burst firing in these cells). These properties are similar to those recently reported for Mo. The anti-agitation effects in patients and the depressant effects of La we report in neural membranes in-vitro are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. These data suggest that components common to the two oils are worthy of focus to identify the actives underlying the neuronal depressant and anti-agitation activities reported. [source] Astaxanthin, a dietary carotenoid, protects retinal cells against oxidative stress in-vitro and in mice in-vivoJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2008Yoshimi Nakajima We have investigated whether astaxanthin exerted neuroprotective effects in retinal ganglion cells in-vitro and in-vivo. In-vitro, retinal damage was induced by 24-h hydrogen peroxide (H2O2) exposure or serum deprivation, and cell viability was measured using a WST assay. In cultured retinal ganglion cells (RGC-5, a rat ganglion cell-line transformed using E1A virus), astaxanthin inhibited the neurotoxicity induced by H2O2 or serum deprivation, and reduced the intracellular oxidation induced by various reactive oxygen species (ROS). Furthermore, astaxanthin decreased the radical generation induced by serum deprivation in RGC-5. In mice in-vivo, astaxanthin (100 mg kg,1, p.o., four times) reduced the retinal damage (a decrease in retinal ganglion cells and in thickness of inner plexiform layer) induced by intravitreal N -methyl- d -aspartate (NMDA) injection. Furthermore, astaxanthin reduced the expressions of 4-hydroxy-2-nonenal (4-HNE)-modified protein (indicator of lipid peroxidation) and 8-hydroxy-deoxyguanosine (8-OHdG; indicator of oxidative DNA damage). These findings indicated that astaxanthin had neuroprotective effects against retinal damage in-vitro and in-vivo, and that its protective effects may have been partly mediated via its antioxidant effects. [source] Preparation and evaluation of a novel delayed-onset sustained-release system of propranolol hydrochlorideJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2008Xue-mei Feng The objective of this work was to prepare and evaluate a new delayed-onset sustained-release system, comprising a sustained-release core tablet with hydroxypropyl methylcellulose as polymer matrix and an ethylcellulose/Eudragit L coating capable of delaying the drug release. The sustained core containing propranolol hydrochloride as the model drug was prepared by granulate tableting and the polymer coating was applied in a computer-controlled coating pan. The dissolution tests demonstrated that the in-vitro drug release was pH-dependent with sufficient gastric resistance, and the lag time (t10%) could be controlled by adjusting the coating level. Three dosage forms including commercial tablet, sustained-release tablet and the delayed-onset sustained-release tablet were administrated to six beagle dogs and the plasma levels of propranolol hydrochloride were measured with high-performance liquid chromatography. The delayed-onset sustained-release tablet had a lag time of 3.0 h in-vitro and 3.5 h in-vivo, and a tmax of 7.0 h. The relative bioavailability for delayed-onset sustained-release tablet was 96.98% compared with commercial tablets. The results indicate that the new propranolol delayed-onset sustained-release system could achieve a relatively constant drug release followed by a programmed lag time, and this may provide a promising drug delivery form for chronopharmacotherapy of certain cardiovascular diseases. [source] Enhancement of nortriptyline penetration through human epidermis: influence of chemical enhancers and iontophoresisJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 4 2008Virginia Merino Different known percutaneous chemical enhancers and iontophoresis have been tested in-vitro to study their ability to increase transdermal absorption of nortriptyline hydrochloride (20 mg mL,1). The chemicals 1-dodecanol, Span 20, Azone, (R)-(+)-limonene or isopropyl myristate were used as an overnight pretreatment at 5% (w/w) in ethanol. Furthermore, isopropyl myristate (20%, w/w) and propylene glycol (15%, w/w) were tested in the same vehicle. Iontophoresis was applied directly to the nortriptyline hydrochloride donor solution for three different concentrations (20, 2 and 0.5 mgmL,1). The chemical enhancers slightly increased the nortriptyline transdermal flux but iontophoresis was more efficient. In this case, nortriptyline transdermal flux was concentration dependent, having a higher flux when the concentration was lowered. Therefore, iontophoresis was the most suitable technique to increase transdermal absorption of nortriptyline and it could be an alternative method to provide therapeutic concentrations of this drug in smoking cessation treatment. [source] Antidiabetic activity of Croton klozchianus in rats and direct stimulation of insulin secretion in-vitroJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2008R. Govindarajan Croton klozchianus is a relatively uninvestigated species with no pharmacological or phytochemical reports available, although it has been used clinically by Ayurvedic physicians to treat diabetes. We have investigated this use by studying the insulin secretion and antidiabetic activity of C. klozchianus. Treatment of diabetic rats with aerial parts of C. klozchianus extract (CK, 100 and 300 mg kg,1 body weight) for three weeks showed significant reduction in blood glucose (45.8% after 14 days for 300 mg kg,1). C. klozchianus extract caused a significant concentration-dependent increase in insulin secretion (8-fold at 2 mg mL,1 for cells challenged with 20 mm glucose) from MIN6 cells grown as monolayers and as pseudoislets, indicating that the antidiabetic activity may have been as a result of increased insulin secretion. It also had a role on the lipid profile of the rats by causing reduction in cholesterol and triglycerides and increasing high density lipoprotein significantly. The results obtained gave some scientific support to the traditional use of the plant as a treatment for diabetes. [source] Pharmacological profile of an essential oil derived from Melissa officinalis with anti-agitation properties: focus on ligand-gated channelsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2008Sawsan Abuhamdah A dual radioligand binding and electrophysiological study, focusing on a range of ligand-gated ion channels, was performed with a chemically-validated essential oil derived from Melissa officinalis (MO), which has shown clinical benefit in treating agitation. MO inhibited binding of [35S] t -butylbicyclophosphorothionate (TBPS) to the rat forebrain gamma-aminobutyric acid (GABA)A receptor channel (apparent IC50 0.040±0.001 mg mL,1), but had no effect on N -methyl- d -aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropianate (AMPA) or nicotinic acetylcholine receptors. Electrophysiological analyses with primary cultures of rat cortical neurons demonstrated that MO reversibly inhibited GABA-induced currents in a concentration-dependent manner (0.01,1 mg mL,1), whereas no inhibition of NMDA- or AMPA-induced currents was noted. Interestingly, MO elicited a significant dose-dependent reduction in both inhibitory and excitatory transmission, with a net depressant effect on neurotransmission (in contrast to the classical GABAA antagonist picrotoxinin which evoked profound epileptiform burst firing in these cells). The anti-agitation effects in patients and the depressant effects of MO in in-vitro we report in neural membranes are unlikely to reflect a sedative interaction with any of the ionotropic receptors examined here. [source] Prediction of human pharmacokinetics , improving microsome-based predictions of hepatic metabolic clearanceJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2007Urban Fagerholm Physiologically based methods generally perform poorly in predicting in-vivo hepatic CL (CLH) from intrinsic clearance (CLint) in microsomes in-vitro and unbound fraction in blood (fu,bl). Various strategies to improve the predictability have been developed, and inclusion of an empirical scaling factor (SF) seems to give the best results. This investigation was undertaken to evaluate this methodology and to find ways to improve it further. The work was based on a diverse data set taken from Ito and Houston (2005). Another objective was to evaluate whether rationalization of CLH predictions can be made by replacing blood/plasma-concentration ratio (Cbl/Cpl) measurements with SFs. There were apparently no or weak correlations between prediction errors and lipophilicity, permeability (compounds with low permeability missing in the data set) and main metabolizing CYP450s. The use of CLint class (high/low) and drug class (acid/base/neutral) SFs (the CD-SF method) gives improved and reasonable predictions: 1.3-fold median error (an accurate prediction has a 1-fold error), 76% within 2-fold-error, and a median absolute rank ordering error of 2 for CLH (n = 29). This approach is better than the method with a single SF. Mean (P < 0.05) and median errors, fraction within certain error ranges, higher percentage with most accurate predictions, and ranking were all better, and 76% of predictions were more accurate with this new method. Results are particularly good for bases, which generally have higher CLH and the potential to be incorrectly selected/rejected as candidate drugs. Reasonable predictions of fu,bl can be made from plasma fu (fu,pl) and empirical blood cell binding SFs (B-SFs; 1 for low fu,pl acids; 0.62 for other substances). Mean and median fu,bl prediction errors are negligible. The use of the CD-SF method with predicted fu,bl (the BCD-SF method) also gives improved and reasonable results (1.4-fold median error; 66% within 2-fold-error; median absolute rank ordering error = 1). This new empirical approach seems sufficiently good for use during the early screening; it gives reasonable estimates of CLH and good ranking, which allows replacement of Cbl/Cpl measurements by a simple equation. [source] Oral peptide delivery: in-vitro evaluation of thiolated alginate/poly(acrylic acid) microparticlesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 9 2007Alexander Greimel ABSTRACT The purpose of this study was to develop an oral thiomer-based microparticulate delivery system for insulin by ionic gelation. The microparticulate matrix consisted of either poly(acrylic acid)-cysteine (PAA-Cys) and alginate-cysteine (Alg-Cys) or the corresponding unmodified polymers (PAA, Alg). Two different viscosities of alginates were provided for the study, low and medium. Three different types of microparticles were prepared via ionic gelation with calcium (Alg, AlgPAA and AlgPAA-Cys) and their different properties evaluated in-vitro (particle size and shape, drug loading and release profile, swelling and stability). The mean particle size of all formulations ranged from 400 to 600 ,m, revealing the lowest for thiolated microparticles. SEM micrographs showed different morphological profiles for the three different types of microparticles. Encapsulation efficiency of insulin increased within the following rank order: Alg (15%) < AlgPAA (40%) < AlgPAA-Cys (65%). Alginate and AlgPAA microparticles displayed a burst release after 30 min, whereas the thiolated particles achieved a controlled release of insulin over 3 h. The swelling ratio was pH dependent: in simulated intestinal fluid microparticles exhibited a much higher water uptake compared with simulated gastric fluid. Due to the formation of intraparticulate disulfide bonds during the preparation process, thiolated particles revealed a higher stability. It was also observed that the viscosity of the two alginates used had no influence on the properties of the particles. According to these results AlgPAA-Cys microparticles obtained by ionic gelation and stabilized via disulfide bonds might be an alternative tool for the oral administration of therapeutic peptides. [source] CJY, an isoflavone, reverses P-glycoprotein-mediated multidrug-resistance in doxorubicin-resistant human myelogenous leukaemia (K562/DOX) cellsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 7 2007Bian-Sheng Ji In an effort to develop safe and effective multidrug-resistance (MDR) reversing agents, the effect of CJY, an isoflavone, on the P-glycoprotein (P-gp) function and P-gp-mediated MDR was evaluated in doxorubicin-resistant human myelogenous leukaemia (K562/DOX) cells. The results showed that CJY caused a marked increase in accumulation and a notable decrease in efflux of rhodamine 123 (Rh123). The inhibitory effect of the agent on P-gp function persisted for at least 120 min after removal of 2.5 ,M CJY from the incubation medium. The doxorubicin-induced cytotoxicity, apoptosis and cell cycle perturbations were significantly potentiated by CJY. The intracellular accumulation of doxorubicin was also enhanced. The compound exhibited potent effects in-vitro on the reversal of P-gp-mediated MDR, suggesting that it could become a candidate as an effective MDR reversing agent in cancer chemotherapy. [source] | |||||||||||||