Targeting of soybean-derived sterylglucoside liposomes to liver tumors in rat and mouse models

A cross-sectional multicentre study was conducted in 165 French diabetic children aged 7-13 y and their parents. A standardized scale (FACES III) was used to determine if family cohesion and adaptability (i) differed in diabetic children's families, as compared to other families; (ii) were related to an adherence measure; or (iii) were related to metabolic control. More diabetic families than comparison families fell into the categories of disengaged with low levels of cohesion, and rigid with low levels of adaptability. Scores of cohesion and adaptability were significantly and positively correlated with both children's and parents' adherence scores, but not with HbA1c levels. Children whose families were characterized as rigidly disengaged had a significantly greater number of hypoglycaemias and six times as many episodes of ketoacidosis than the other diabetic children. Not only in adolescents, but also in families of diabetic children, family-centred interventions are needed to improve compliance and to prevent acute metabolic complications.     

Preparation and characterization of collagen coated cholesterol-free liposome nanoparticles matrix for drug carriers and tissue engineering application

The collagen coated cholesterol (CH)-free liposome nanoparticle (CCLNP) matrix has been prepared and characterized for use as therapeutic drug carriers, tissue engineering and regenerative medicinal applications. The CH-free liposome nanoparticle (LNP) was prepared by heating method under the N2 atmosphere and CCLNP matrix was prepared by incubation of bovine Achilles tendon collagen with preformed CH-free LNP. The results indicate that collagen stabilizes the original liposomal structure, and CCLNP are more stable in vitro than control liposome. This mineralized collagen composite matrix could be useful to bone and dental implants.     

The potential of liposomes in oral drug delivery

Oral liposome drug delivery has been the subject of much cynicism. Results have been quite variable and, for the most part, have not been predicated on specific objectives that would lead to success. Prerequisites are stability in the gastrointestinal environment and binding to specific sites. Transport via paracellular and transcellular routes from normal epithelial tissue or Peyer's patches leads to different outcomes of drug delivery and immunization, respectively. Polymerized, microencapsulated, and polymer-coated liposomes have all increased the potential of oral liposomes. Using targeted liposomes and a greater understanding of their cellular processing will ultimately lead to effective therapies from oral liposomes.     

Physico-chemical characterization of the spectrin tetramer from bovine erythrocyte membranes

The tetramer of bovine spectrin has been purified and characterized in terms of its hydrodynamic and optical properties. (1) The molecular weight, from both sedimentation equilibrium and sedimentation velocity/diffusion measurements, is close to one million. (2) The hydrodynamic properties suggest a highly expanded but basically symmetrical molecule of Stokes radius 200 A. (3) Optical rotatory dispersion measurements indicate a high degree of order in the tertiary structure of the molecule. These results are not consistent with the assumption that is often made, that the spectrin molecule is a long fibrous rod.     

Preparation and characterization of 8a-(phosphatidylcholine-dioxy)-alpha-tocopherones and their formation during the peroxidation of phosphatidylcholine in liposomes

alpha-Tocopherol was reacted with the phosphatidylcholines (PCs), 1-palmitoyl-2-linoleoyl-3-sn-PC (PLPC), 1-palmitoyl-2-linolenoyl-3-sn-PC, 1-palmitoyl-2-arachidonoyl-3-sn-PC (PAPC) and 1-stearoyl-2-arachidonoyl-3-sn-PC, in the presence of the free radical initiator, 2,2'-azobis (2,4-dimethylvaleronitrile), at 37 degrees C. The addition products of alpha-tocopherol with the PC peroxyl radicals were isolated and identified as 8a-(PC-dioxy)-alpha-tocopherones, in which the peroxyl radicals derived from each PC molecule attacked the 8a-position of the alpha-tocopheroxyl radical. The antioxidative efficiency of alpha-tocopherol against the peroxidation of PLPC and PAPC in liposomes was assessed by the formation of the reaction products of alpha-tocopherol. When alpha-tocopherol was oxidized in the presence of the water-soluble free radical initiator, 2,2'-azobis (2-amidinopropane) dihydrochloride, epoxy-alpha-tocopherylquinones were mainly produced together with 8a-(PC-dioxy)-alpha-tocopherones and alpha-tocopherylquinone. The yield of alpha-tocopherylquinone was increased by treating each sample with dilute acid which indicates the presence of tocopherone precursors other than the 8a-(PC-dioxy)-alpha-tocopherones. The same products were also detected from iron-dependent peroxidation, although the yields were very low.     

Synthesis, characterization, biodegradation, and drug delivery application of biodegradable lactic/glycolic acid oligomers: Part II. Biodegradation and drug delivery application

The construct of impulsivity has to date remained relatively unexplored in the pathological gambling literature. This is in spite of recent claims suggesting that impulsivity may be an important feature characterizing a subgroup of pathological gamblers who are claimed to suffer from a Multi-Impulse Personality Disorder. The present study examined the potential role of impulsivity using the Eysenck Impulsivity Scale among 115 pathological gamblers. Results indicate that heightened impulsivity is associated with the degree of severity of psychological and behavioural change in pathological gamblers. However, the findings also indicate that impulsivity closely mirrors components contained in Eysenck Personality Questionnaire Psychoticism Scale, the California Personality Inventory Socialization Scale and DSM-III Antisocial Personality Disorder. This is manifest both in terms of high intercorrelations between the measures of psychopathy and impulsivity and in their predictive relationship to the level of psychological distress suggesting a uniform impulsivity/psychopathy construct. Thus, the research supports a model of pathological gambling in which the severity of associated behavioural and psychological disturbance is mediated by a impulsivity/ psychopathy construct.     

Physico-chemical characterization, preparation and performance of poly (methylidene malonate 2.1.2) nanoparticles

The present investigation confirms that initially implemented procedure to produce poly(methylidene malonate 2.1.2) (PMM 2.1.2) nanoparticles (Lescure et al. Pharm Res 1994;11:1270-77) lead to products mostly containing plasticizing oligomers which strongly lowered glass-transition temperature (Tg), dramatically reduced nanoparticle consistency and rendered them too sensitive to solubilization when diluted in an aqueous medium. From MALDI-TOF spectroscopy analysis, performed on intact colloids, emerged some structural information about these oligomeric species which could result from an intramolecular cyclization mechanism occurring soon in the course of the polymerization process. Thus, with the objective of overcoming these drawbacks, this contribution deals with the variations of manufacturing specifications such as pH and magnetic stirring speed to try and modulate molecular weight (MW) of nanoparticle constituents and reduce oligomer concentration. Although the analyses performed on these new nanoparticles were rather encouraging, the colloid formation yield became so low that it required the development of other methodologies, excluding a previous emulsion step, and allowing a controlled production of PMM 2.1.2-made nanoparticles having better physico-chemical characteristics while keeping good pharmaceutical capabilities.     

Accumulation of protein-coated liposomes in an extravascular site: influence of increasing carrier circulation lifetimes

The primary objective of this work was to test whether increased blood levels and circulation lifetimes result in increased passive targeting of protein-coated liposomal drug carriers. The system used to evaluate this was based on i.v. injection of 100 nm of distearoyl phosphatidylcholine/cholesterol liposomes with covalently bound streptavidin. The circulation lifetime of these liposomes was increased by procedures that involved blockade of liposome uptake by phagocytic cells in the liver and/or the incorporation of a poly(ethylene glycol)-modified phospholipid [poly(ethylene glycol)2000-modified distearoyl phosphatidylethanolamine]. Blockade of liver phagocytic cells with a low predose (2 mg/kg of drug) of liposomal doxorubicin increased the circulation half-life of the streptavidin liposomes from less than 1 hr to greater than 3 hr. A further 2-fold increase in circulating half-life (to approximately 7.5 hr) was achieved by using liposomes with 2 mole % of poly(ethylene glycol)2000-modified phosphatidylethanolamine. In combination with RES blockade, the circulation lifetimes of poly(ethylene glycol)phosphatidylethanolamine containing streptavidin liposomes could be increased to greater than 12 hr. The ability of these liposomes to move from the plasma compartment to an extravascular compartment was measured by using the peritoneal cavity as a convenient, accessible, extravascular site. The tendency for liposomes to accumulate in this site was not, however, clearly dependent on circulating blood levels. Comparable levels of liposomes in the peritoneal cavity were achieved when using systems that exhibited significantly different circulation lifetimes.     

Competitive protein-binding assay for somatomedins and their carrier protein (author's transl)

Rat liver explants in culture release a protein which has a molecular weight of approximately 65,000 and both an affinity and a specificity for somatomedins (SMs) similar to that of the carrier protein found in human serum. A competitive binding assay has been set up using this protein and purified NSILA-S, with a sensitivity threshold of 0.05 mu U NSILA-S. By means of gel filtration in acetic acid of the biological samples, SMs and their carrier protein are separated and the two parameters can therefore be measured within the same sample. Purified preparations of NSILA-S and SM-A, and endogenous SMs extracted from various mammalian sera and from rat liver culture medium give parallel dose-response curves. The mean SM concentrations in human serum, expressed in terms of mu U NSILA-S/ml were 199 +/- 10.8 (SE) in 9 normal adults, 19 +/- 2.7 in 18 hypopituitary patients and 255 +/- 14 in 18 acromegalics. Compared with the levels in normal subjects, acromegalic had high, and hypopituitary patients low carrier protein concentrations.     

Physicochemical characterization of bisphosphonic carboxyfluorescein for osteotropic drug delivery

We present the case of a woman who had an Accufix atrial "J" pacemaker lead implanted in 1990. Subsequently, Telectronics Pacing Systems recalled two models of the atrial leads after problems with fracture and malfunction were reported. One of these models was used in our case. Fifty-two months after implantation, following recommended fluoroscopic screening, our patient was found to have a complete fracture of the "J" retention wire with one fragment protruding from the sheath in the right atrium and another fragment of the wire lodged in the right ventricle. The pacemaker had continued to function normally and there was no clinical evidence to suggest such a potentially disastrous fracture. Our report emphasizes the importance of fluoroscopic screening of all patients with atrial leads involved in the recall.     

Development of ciprofloxacin-loaded nanoparticles: physicochemical study of the drug carrier

This paper describes the optimization of the preparation of ciprofloxacin-loaded polyethylbutylcyanoacrylate (PEBCA) nanoparticles. The association of ciprofloxacin with nanoparticles was performed by emulsion polymerization, but successful entrapment was only obtained in the presence of acetone in the polymerization medium. This preparation process led to a stable ciprofloxacin nanoparticle suspension, with a mean size value twice as high as that obtained in the absence of drug, and an association efficiency of 82%. Moreover, the molecular weight value of ciprofloxacin nanoparticles was shown to be reduced as compared with unloaded nanoparticles. Drug release from the colloidal carrier in medium containing esterase was found to be very slow (a maximum of 51.5% after 48 h), suggesting that this release resulted from bioerosion of the polymer matrix. Interestingly, it was observed that 30.5% of the initial amount of ciprofloxacin was not detectable by HPLC analysis after nanoparticle preparation and corresponded either to ciprofloxacin covalently bound to PEBCA or to ciprofloxacin chemically degraded during the polymerization process. 19F-NMR analysis demonstrated that ciprofloxacin entrapped into nanoparticles was only in its neutral form. The measurements of molecular weight suggest the participation of the antibiotic as an anionic polymerization initiator, leading to the formation of a chemical bond between some of the drug and the polymer. These data allowed us to propose a model describing the association of ciprofloxacin with PEBCA nanoparticles obtained by emulsion polymerization.     

抗生素的耐药性与抗生素的应用

细菌对抗生素产生耐药性是一种自然生物现象,抗生素的广泛应用与滥用加速了耐药性过程.现就抗生素的耐药机理进行讨论,期望有助于进一步合理应用抗生素.     

Oxidases of l-amino acids and outlook for their practical application

The sources of production of aminoacyl oxidases, their principal biochemical properties have been considered. The role of lysine oxidase in the mechanism of DNA, RNA inhibition in some forms of the tumor cells in vivo has been discussed. The prospects of the enzyme use in the analytical practice and medicine are presented.     

Preclinical characterization of an anti-tat ribozyme for therapeutic application

A hammerhead ribozyme retroviral construct, denoted RRz2, targeting the coding region of the human immunodeficiency virus type 1 (HIV-1) tat gene, has shown itself to be effective in a range of test systems. Inhibition of the replication of HIV-1 IIIB and primary drug-resistant strains in pooled transduced CEMT4 cells was consistently found to be more than 80% compared with the control-vector transduced cells, whereas a mutant RRz2 gave approximately 45% inhibition. A multiple HIV-1 passage assay showed the absence of emergence of mutations within the specific viral RNA ribozyme target sequences. This lack of generation of ribozyme "escape mutants" occurred despite the almost complete disappearance of a HIV-1 quasi-species in the testing virus. When RRz2 was tested in peripheral blood lymphocytes (PBLs) from HIV-1-infected patients, paired analysis showed that cell viability in the ribozyme-transduced HIV-1-infected PBLs was significantly higher than that in the vector-transduced cells. This difference in viability (vector versus RRz2) was not observed in PBLs from non-HIV-1-infected donors. Taken together, these results indicate that the transfer of an anti-HIV-1 ribozyme gene into human T lymphocytes could have major impact on viral replication and T cell viability in the HIV-1-infected individual.     

Liposomes disposition in vivo. V. Liposome stability in plasma and implications for drug carrier function

The kinetics of [14C]sucrose release from multilamellar liposomes of fixed diameter (approx. 0.23 micron) incubated in human plasma (serum and blood) were quantified. Composition was various ratios of phosphatidylcholine, phosphatidic acid and cholesterol with alpha-tocopherol included as antioxidant. Considerable intra-individual variability was noted for liposome stability in blood and its derived fluids, yet reproducible results were obtained for pooled samples. The destabilizing effects of plasma decreased with increasing lipid concentrations. Results of fitting a kinetic model to the data showed that four of five model parameters were linearly related to liposome cholesterol content. Liposomes depleted plasma of its destabilizing factors, and when pre-incubated with plasma were partially stabilized to the effects of a subsequent plasma addition. Plasma caused a rapid rise in liposome membrane permeability which then declined non-linearly, presumably because of a rearrangement of membrane lipids and adsorbed proteins to form their most stable configuration. The therapeutic availability of drugs administered encapsulated in liposomes, which can be governed by the kinetics of their in vivo extracellular release, may be directly proportional to--and predictable from--the time-course and extent of release in plasma. The kinetic model was used in conjunction with simple pharmacokinetic assumptions to show that the effectiveness of a liposome drug carrier cannot be predicted based simply on its plasma stability; more stable liposomes may not be more effective drug carriers. Interestingly, plasma-induced solute release from liposomes serendipitously mimics an important facet of ideal carrier behavior.     

Identification and partial characterization of the high-affinity choline carrier from rat brain striatum

[3H]Choline mustard aziridinium ion binds irreversibly to the sodium-coupled high-affinity choline transport protein in a sodium-dependent and hemicholinium-sensitive manner, and thus is a useful affinity ligand. In rat striatal synaptosomal membranes, it radiolabels two polypeptides with apparent molecular masses of 58 and 35 kDa. Based upon the use of two different experimental approaches, it appears that neither of these polypeptides is glycosylated.     

Low swelling, crosslinked guar and its potential use as colon-specific drug carrier

PURPOSE: (a) To reduce the swelling properties of guar gum (GG) by crosslinking it with glutaraldehyde (GA), while maintaining its degradation properties in the presence of typical colonic enzymes, (b) to characterize the modified GG and to examine its degradation properties in vitro and in vivo, and (c) to assess, by drug probes with different water solubilities, the potential of the crosslinked GG to serve as a colon-specific drug carrier. METHODS: GG was crosslinked with increasing amounts of GA under acidic conditions to obtain different products with increasing crosslinking densities. These products were characterized by measuring (a) their swelling properties in simulated gastric and intestinal fluids, (b) their crosslinking densities, (c) the release kinetics of three different drugs: sodium salicylate (SS), indomethacin (Indo) and budesonide (Bud) from the crosslinked products into buffer solutions, with or without a mixture of galactomannanase and alpha-galactosidase, and (d) their in vivo degradation in the cecum of conscious rats with and without antibiotic treatment. RESULTS: Significant reduction in GG swelling properties, in both simulated gastric and intestinal fluids, was accomplished by its crosslinking with GA. The crosslinking density of the modified GG products was GA concentration-dependent. The release of SS from crosslinked GG discs was completed within 120 minutes. During the same period of time and for more than 10 hours the release of Indo and Bud was negligible. The release rate of the latter two drugs was enhanced when galactomannanase and alpha-galactosidase were added to the dissolution media. Discs made of the crosslinked GG were implanted in the cecum of rats and their degradation was assessed after 4 days. The extent of degradation was dependent on the amount of GA used for the crosslinking. After 4 days the same discs were recovered intact from rats exposed to antibiotic treatment and from simulated gastric and intestinal fluids. CONCLUSIONS: Reducing the enormous swelling of GG by crosslinking it with GA resulted in a biodegradable hydrogel which was able to retain poorly water soluble drugs, such as Indo and BUD, but not highly water soluble drugs, such as SS, in artificial gastrointestinal fluids. A variety of hydrogels with increasing crosslinking densities were produced and tested for their potential use as colon-specific drug platforms in vitro and in vivo. Their performance did not depend on creating physical barriers by means of compression.     

Al-Si@Al2O3核壳结构载体的制备及其催化应用

以微米级铝硅（Al-Si）合金粉为原料,采用简单的水热反应,设计开发出一种以鳞片状Al2O3为壳、Al-Si 合金为核的催化剂载体（Al-Si@Al2O3）。通过傅里叶红外分析（FT-IR）、X 射线衍射（XRD）、扫描电镜（SEM）及透射电镜（TEM）等表征分析表明,经过水热反应后,Al-Si 合金表面原位生成片状的AlOOH,内核为未反应的Al-Si合金,500℃煅烧后浸渍载Pd制备出Pd/Al-Si@Al2O3催化剂,活性组分Pd粒子均匀分散在载体表面。以苯乙烯加氢为探针反应考察Al-Si合金原料的粒径、铝含量等因素对所制备催化剂性能的影响,同时还与水浴、碱处理及酸处理所制备的载体和传统载体活性炭、活性氧化铝进行比较。结果表明,在水热条件下,以粒径为5μm、铝含量为88%的Al-Si合金粉为原料制备的Pd/Al-Si@Al2O3具有较优的催化性能,且其催化活性优于活性炭和活性氧化铝载Pd催化剂。