摘要:

AbstractIn an attempt to reduce the surface charge of cationic liposomes, and thereby increase their transfection efficiencies, the effect of the amphiphilic solvation enhancer dipalmitoylphosphatidylethanolaminyl‐poly‐(ethylene glycol) (DPPE‐PEG) on the stability of cationic dioleoylphosphatidylethanolamine (DOPE) dioleoyltrimethylammonium propane (DOTAP) liposomes, their interaction with DNA and the aggregation of liposomal DNA complexes by anionic proteins has been evaluated by photon correlation spectroscopy and measurement of liposome ζ potential.DOPE‐DOTAP liposomes were unstable, and exhibited significant aggregation after seven days storage at 4°C. DOPE‐DOTAP liposomes containing DPPE‐PEG (5 mol%) were more stable, but also showed some aggregation. DOPE‐DOTAP liposomes had a ζ potential of + 34 mV This was significantly reduced to a value of +6 mV by the incorporation of DPPE‐PEG. Both liposome formulations reacted with DNA at weight ratios of 1:1 to 15:1 within 1–5 min at pH 7‐4 and 23°C. The ζ potential of DOPE‐DOTAP liposomes was significantly reduced by genomic and plasmid DNA, in a dose‐dependent manner, to give a ζ potential of + 3 mV at a liposome‐to‐DNA ratio of 1:1. The ζ potential of DOPE‐DOTAP‐DPPE‐PEG liposomes was further reduced by DNA to − 9 mVat a liposome‐to‐DNA ratio of 1:1. Incubation of DOPE‐DOTAP liposomal plasmid DNA (1:5 ratio) with the anionic proteins albumin or IgG, or with a buccopharyngeal wash resulted in a rapid and significant aggregation (0–18 μM to 1–2 μM) accompanied by significant reductions in ζ potential. In contrast, DOPE‐DOTAP‐DPPE‐PEG liposomes showed only a slight increase in size that was not accompanied by a significant change in ζ potential.These results indicate that although DPPE‐PEG masks the positive charge of DOTAP at the liposome surface and thus reduces electrostatic interaction with anionic proteins, it still ena

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00561.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractTo develop a profile for the activity of lipopolysaccharides on guinea‐pig lung tissue, previous in‐vitro studies have been expanded to include a new model where the necessity to expose live animals is eliminated.Isolated lung halves were perfused and tracheal spirals were immersed in Krebs solution containing lipopolysaccharides. One hour after exposure both the tracheal and pulmonary tissues were hyper‐responsive to all the constrictor agents employed. This was demonstrated by the dose‐response curves being shifted significantly to the left parallel to control curves. The shifts seen were comparable with those observed for bronchoconstriction after in‐vivo exposure.The results confirm that the change in airway reactivity seen after exposure to lipopolysaccharide is nonspecific and is likely to be a result of a change in reactivity of the airway smooth muscle caused either directly or indirectly by, for example, agents released from alveolar macrophages, airway epithelium or pulmonary endothelium. Changes in airway reactivity are not entirely a result of narrowing of the airway, but can arise as a result of accumulation of fluid in the airways or alteration of the function of the nasal passages of the guinea‐pig (an obligatory nos

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00562.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractExposure to respirable dust from the cotton plant during fibre manufacture is associated with the occupational lung disease byssinosis in textile mill workers. We describe an animal model to evaluate the role of mucociliary clearance mechanisms during acute exposure to cotton.The pulmonary clearance of an inhaled aerosol of tin particles radiolabelled with99mTechnetium was monitored in guinea‐pigs by gamma‐scintigraphy. The ability of the lung to clear labelled tin particles was examined after inhalation of an aqueous extract of cotton dust over a five‐day treatment period. After exposure to cotton‐dust extract, the percentage activity retained in the lung 2 h after inhalation of the marker was significantly (P= 0.01) lower than observed in the same group of animals before treatment.This suggests that in an animal model, mucociliary clearance is stimulated by acute exposure to cotton dust, which may serve as a protective mechanism in the lung. This appears to be a valid technique for the measurement of the mucociliary clearance of inhaled particles, which is a factor in pulmonary

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00563.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe study was undertaken to examine whether chronic repeated challenge of sensitized guinea‐pigs with antigen would induce hyper‐reactivity to the spasmogen U46619 (9,11‐dideoxy‐11α,9α‐epoxymethanoprostaglandin F2α).Airway function was measured in conscious guinea‐pigs by whole‐body plethysmography; leucocyte infiltration into the lungs was monitored using bronchoalveolar lavage. Male guinea‐pigs were sensitized to ovalbumin by injection (i.p.) of a suspension (1 mL) containing ovalbumin (10 μg) and aluminium hydroxide (100 mg); they were used 14 days later. In sensitized guinea‐pigs repeated inhaled antigen challenges (0.5% ovalbumin in saline for 10 min twice weekly for 4 weeks) induced a state of pulmonary inflammation characterized by an enhanced and prolonged late‐phase response and a persistent eosinophilia. Inhalation of a threshold dose of the thromboxane‐mimetic, U46619 (30 ng mL−1for 60 s), 72 h after the final saline challenge of control animals caused a threshold bronchoconstriction. Seventy two hours after the final antigen challenge, however, there was a marked bronchodilation to U46619. A persistent hyper‐reactivity was expected. Ro 20–1724 (3 mg kg−1i.p. before and 6 h after each antigen challenge), a selective inhibitor of phosphodiesterase type IV, attenuated both early and late asthmatic responses and the airway eosinophilia associated with this chronic antigen challenge model. There was no evidence of a bronchodilatory response to the same dose of inhaled U46619 in the group treated with Ro 20–1724.These results suggest that inhaled low dose U46619 induces a bronchodilation when delivered to conscious guinea‐pigs after a series of repeated antigen challenges and when the airways are presumably in a state of chronic inflammation. This effect is lost when the airway inflammation is attenuated by the concurrent administration of Ro 20–1724.

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00564.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractTo determine whether the biological activity of lutein and 8‐methoxypsoralen are related to their effect on membrane lipids, their effects, in the dark, on liposomal and erythrocyte membranes were studied by electron paramagnetic resonance (by use of a spin label), by ultrasound absorption, and by differential scanning calorimetry.Incorporation of lutein or 8‐methoxypsoralen into erythrocyte membranes increased the fluidity of the membrane in the lipid core adjacent to the hydrophilic zone (as monitored with 5‐doxyl‐stearic acid spin label). Both compounds also increased ultrasound absorption in dipalmitoylphosphatidylcholine liposomes and reduced the temperature of the main phase transition.These results indicate that despite their different chemical structures and their different localization in the membrane, on a molecular level the mode of action of these two drugs on biomembranes is very

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00565.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe relative configurations of some low‐molecular‐weight hormones and guanosine triphosphate are similar. Because adenosine and guanosine nucleotides, in cyclic and non‐cyclic forms, participate in hormone receptor activation mechanisms, this investigation of molecular similarity has been extended to both purine nucleotides and ligands operating at histamine receptor sub‐types.Nitrogen atoms in mono‐cation minimum energy conformers of histamine and H1agonists relate to a specific pattern of nitrogen atoms in the guanine ring. Nitrogen atoms in uncharged minimum energy conformers of histamine H2and H3agonists relate to a different pattern of nitrogen atoms in the adenine ring. Minimum energy conformers of H1, H2and H3antagonists fit to specific nitrogen atoms in the same purine ring system as their corresponding agonist. Structural similarity, relevant to H1receptor activation, is also evident in histamine and arginine molecules.Histamine receptor design may be based on purine nucleotide structure. Histamine H1receptors demonstrate complementarity for the guanine ring. Histamine H2and H3receptors show complementarity for the adenine ri

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00566.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractAZT is effective in prolonging survival and reducing the frequency and severity of opportunistic infections, but no preparation of the compound is available for sustained delivery. Poly(lactide‐co‐glycolide) microcapsules containing AZT have been prepared by a novel phase separation technique.Poly(dl‐lactic/glycolic acid) (PLGA) was dissolved in dichloromethane; the drug was added to the solution which was then sonicated for 30 s. The polymer‐drug mixture was added dropwise to a solution of silicone oil in dichloromethane with continuous stirring using a magnetic stirrer. Stirring was maintained until the dichloromethane had completely evaporated to give microcapsules which were then washed with cold petroleum ether, filtered, and freeze‐dried to give a free‐flowing powder. The microcapsules prepared by this method were smooth, spherical, and agglomerated; the particle size was between 25 and 300 μm. The efficiency of encapsulation was more than 90%. An in‐vitro drug‐release study showed that the microcapsules were free from any initial “burst effect”. An excellent sustained release was observed from the microcapsules up to 17 days followed by a burst effect between 17 and 22 days. Drug release, however, continued over a 60‐day period.The phase separation method significantly improved the efficiency of encapsulation of AZT in PLGA. Although the microcapsules prepared by this method showed no initial burst effect, significant dose dumping was observed between the second and third week as a result of the rap

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00567.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractMonodisperse, non‐ionic surfactants based on lysine contain two hydrophobic chains and one or two polyoxyethylene glycol chains with a methoxy group capping the terminal hydroxyl function. Because their structural resemblance to lecithins suggests they could be regarded as non‐ionic molecular mimics of these compounds, their haemolytic action has been studied.The presence of 14 and 18 carbon atoms in the hydrophobic moiety seems to result in greater haemolytic action of the surfactants with one polyoxyethylene glycol chain. In the series with two polyoxyethylene glycol chains, the compounds tested at a concentration higher than their critical micellar concentration have greater haemolytic effect, irrespective of the shape of the micelles. When there is a single polyoxyethylene chain a relationship is observed between chain length and haemolytic effect. This correlation is not observed for compounds with two chains.The results show that it is not always possible to predict the haemolytic effect of a surfactant on the basis of its structure and composit

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00568.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe effects of tilisolol hydrochloride, a new β‐blocker, on the activation of the adenosine 5′‐triphosphate (ATP)‐sensitive K+channel (KATPchannel) has been investigated using the patch‐clamp technique.In cell‐attached patch configurations, 0·3 μM tilisolol hydrochloride significantly activated the KATPchannel of cultured porcine coronary artery smooth muscle cells. In excised inside‐out patch configurations, tilisolol hydrochloride activated the KATPchannel in a concentration‐dependent manner in the presence, but not the absence, of 100 μm adenosine 5′‐diphosphate (ADP). In the presence of 100 μM ADP, the open probabilities of the KATPchannels were significantly increased from 0·032±0·006 to 1·314±1·162 (n = 4,P<0·05) by addition of 10 μM tilisolol hydrochloride. We also studied this ADP‐dependency of the K+‐channel openers, nicorandil, levcromakalim and pinacidil. Like tilisolol hydrochloride, nicorandil also activated the KATPchannel in the presence, but not the absence, of ADP. Levcromakalim and pinacidil activated the KATPchannel even without ADP.The finding that tilisolol hydrochloride required ADP to activate the KATPchannel in excised inside‐out patch configurations suggests that tilisolol hydrochloride is an ADP‐dependent KATP‐channel opener like nicorandil, and unlike levcromakalim and pinacidil. Thus, KATP‐channel openers may be distinguished by their dep

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00569.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY

摘要:

AbstractThe 5‐hydroxytryptamine‐transport inhibitor fluoxetine interferes with the hepatic metabolism of many drugs and can potentiate the effects of anaesthetics. Because of the significance of this behaviour and because previous reports are inconsistent, the effect has been further investigated. Rats given fluoxetine (15 mg kg−1, i.p.) for six days did not regain consciousness after sodium pentobarbital anaesthesia (65 mg kg−1, i.p.). Serum pentobarbital levels were increased by 50% by fluoxetine (10 mg kg−1, 24 and 16 h before pentobarbital, 30 mg kg−1), and fluoxetine (0–10 mg kg−1) dose‐dependently (ED50 = 2·9±0·5 mg kg−1) increased nocturnal behavioural sedation induced by pentobarbital (50 mg kg−1, 4 h later). Gastrointestinal abnormalities and weight loss also were found after repeated fluoxetine administration, particularly intraperitoneally.These observations indicate that fluoxetine can lethally potentiate pentobarbital anaesthesia, and suggest additional adverse effects of repeated

ISSN:1460-8081    

DOI:10.1111/j.2042-7158.1996.tb00570.x

出版商:Blackwell Publishing Ltd    

年代:1996

数据来源: WILEY