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1.
Dr Nandini V. Katre 《American Journal of Drug Delivery》2004,2(4):213-227
Liposomes have proven to be versatile carriers for the delivery of drugs. These carriers are biocompatible, since they are generally made from lipids commonly found in biologic systems and are biodegradable by the usual metabolic pathways. A sustained drug delivery system is useful when the efficacy of drugs is limited by the inability to maintain therapeutic concentrations. Furthermore, a depot delivery system can offer important advantages in the clinic, such as significantly reducing dose frequency and providing efficacy without toxicity. Because of their small size (<5μ.m), conventional liposomes (unilamellar and multilamellar) are limited in their ability to provide depot delivery of drugs when administered subcutaneously or intramuscularly. The small size of these liposomes results in relatively fast clearance from the injection site and a short duration of delivery, typically 1–4 days. Multivesicular liposomes (MVLs) are distinct from conventional liposomes in composition, structure, and size and are the only class of commercial liposomes that have demonstrated depot delivery of both small molecule and protein/peptide drugs. These MVLs are characterized by the presence of a continuous bilayer membrane, with numerous internal aqueous compartments that are contiguous and separated by bilayer septums. As a result of their larger size (median diameter typically 10–30μ.m), these MVLs are not rapidly cleared by tissue macrophages and can act as a drug depot providing slow release of drugs delivered through different routes of administration. Moreover, the biocompatibility and biodegradability of the MVL lipid matrix allows for the sustained delivery of drugs to sensitive areas. The unique architecture of MVLs provides high drug loading of water-soluble drugs, reasonable stability during storage, and control over the drug-release rate. Furthermore, the lipid composition of MVLs can be altered to deliver therapeutics over periods ranging from a few days to a month, in order to meet specific therapeutic needs. The capability of altering the rate of drug release from MVLs by varying the lipid composition provides a great deal of versatility for controlled delivery of a wide variety of therapeutics. This article reviews depot delivery with conventional liposomes, demonstrates through several examples the sustained depot delivery of small and macromolecular drugs using MVLs, and summarizes some novel delivery systems that combine liposomes with polymeric matrices and have the potential to expand the platform of liposomal depot delivery. 相似文献
2.
3.
Ian R Reid Paul D Miller Jacques P Brown David L Kendler Astrid Fahrleitner‐Pammer Ivo Valter Katre Maasalu Michael A Bolognese Grattan Woodson Henry Bone Beiying Ding Rachel B Wagman Javier San Martin Michael S Ominsky David W Dempster 《Journal of bone and mineral research》2010,25(10):2256-2265
Denosumab, a human monoclonal antibody against RANKL, reversibly inhibits osteoclast‐mediated bone resorption and has been developed for use in osteoporosis. Its effects on bone histomorphometry have not been described previously. Iliac crest bone biopsies were collected at 24 and/or 36 months from osteoporotic postmenopausal women in the FREEDOM study (45 women receiving placebo and 47 denosumab) and at 12 months from postmenopausal women previously treated with alendronate in the STAND study (21 continuing alendronate and 15 changed to denosumab at trial entry). Qualitative histologic evaluation of biopsies was unremarkable. In the FREEDOM study, median eroded surface was reduced by more than 80% and osteoclasts were absent from more than 50% of biopsies in the denosumab group. Double labeling in trabecular bone was observed in 94% of placebo bones and in 19% of those treated with denosumab. Median bone‐formation rate was reduced by 97%. Among denosumab‐treated subjects, those with double labels and those with absent labels had similar levels of biochemical markers of bone turnover. In the STAND trial, indices of bone turnover tended to be lower in the denosumab group than in the alendronate group. Double labeling in trabecular bone was seen in 20% of the denosumab biopsies and in 90% of the alendronate samples. Denosumab markedly reduces bone turnover and also reduces fracture numbers. Longer follow‐up is necessary to determine how long such low turnover is safe. © 2010 American Society for Bone and Mineral Research. 相似文献
4.
Katre A Ballinger C Akhter H Fanucchi M Kim DK Postlethwait E Liu RM 《Inhalation toxicology》2011,23(8):486-494
Ozone (O?), a commonly encountered environmental pollutant, has been shown to induce pulmonary fibrosis in different animal models; the underlying mechanism, however, remains elusive. To investigate the molecular mechanism underlying O?-induced pulmonary fibrosis, 6- to 8-week-old C57BL/6 male mice were exposed to a cyclic O? exposure protocol consisting of 2 days of filtered air and 5 days of O? exposure (0.5 ppm, 8 h/day) for 5 and 10 cycles with or without intraperitoneal injection of IN-1233, a specific inhibitor of the type 1 receptor of transforming growth factor beta (TGF-β), the most potent profibrogenic cytokine. The results showed that O? exposure for 5 or 10 cycles increased the TGF-β protein level in the epithelial lining fluid (ELF), associated with an increase in the expression of plasminogen activator inhibitor 1 (PAI-1), a TGF-β-responsive gene that plays a critical role in the development of fibrosis under various pathological conditions. Cyclic O? exposure also increased the deposition of collagens and alpha smooth muscle actin (α-SMA) in airway walls. However, these fibrotic changes were not overt until after 10 cycles of O? exposure. Importantly, blockage of the TGF-β signaling pathway with IN-1233 suppressed O?-induced Smad2/3 phosphorylation, PAI-1 expression, as well as collagens and α-SMA deposition in the lung. Our data demonstrate for the first time that O? exposure increases TGF-β expression and activates TGF-β signaling pathways, which mediates O?-induced lung fibrotic responses in vivo. 相似文献
5.
Schedule dependency of the antitumor activity and toxicity of polyethylene glycol-modified interleukin 2 in murine tumor models 总被引:1,自引:0,他引:1
R J Zimmerman S L Aukerman N V Katre J L Winkelhake J D Young 《Cancer research》1989,49(23):6521-6528
Modification of recombinant human interleukin 2 (rhIL-2) with monomethoxy polyethylene glycol has been shown to alter its pharmacokinetic properties. Therefore, we investigated the pharmacological parameters of schedule and dose in order to assess the impact on the in vivo antitumor activity of this modification. The antitumor efficacy, as well as the toxicity, of polyethylene glycol-interleukin 2 (PEG-IL-2) was compared to that of rhIL-2 in three transplantable syngeneic murine tumor models, Meth A fibrosarcoma, B16 melanoma, and Pan-02 pancreatic carcinoma. At equitoxic dose levels, the antitumor activity of PEG-IL-2 was far superior to that of rhIL-2 in all three tumor models. This efficacy of PEG-IL-2 was dose dependent and was greatest on a Q7D x 2 schedule in Meth A and B16. When the same total doses were further divided and delivered on any of several alternative schedules, either the efficacy was reduced or the toxicity of the treatments was increased. In Pan-02, a rhIL-2-resistant tumor, PEG-IL-2 treatment on either the Q7D x 2, Q4D x 3, or Q3D x 4 schedule resulted in approximately a 200% increase in lifespan; however, the toxicity of the treatment increased as the interval between doses was shortened. Simulations of the pharmacokinetic profiles of these various regimens suggested that the toxicity of PEG-IL-2 and rhIL-2 was related to the minimum plasma concentration that was obtained and the time interval between peak levels. The efficacy of the treatment was associated with the interleukin 2 plasma peak height, since a dose response was observed; however, peak plasma concentration did not appear to be the only parameter which determined efficacy. We hypothesize that this observed schedule dependence is also affected by the kinetics of the host's biological response to rhIL-2. 相似文献
6.
Toxicity of Ag, CuO and ZnO nanoparticles to selected environmentally relevant test organisms and mammalian cells in vitro: a critical review 总被引:1,自引:0,他引:1
Olesja Bondarenko Katre Juganson Angela Ivask Kaja Kasemets Monika Mortimer Anne Kahru 《Archives of toxicology》2013,87(7):1181-1200
Nanoparticles (NPs) of copper oxide (CuO), zinc oxide (ZnO) and especially nanosilver are intentionally used to fight the undesirable growth of bacteria, fungi and algae. Release of these NPs from consumer and household products into waste streams and further into the environment may, however, pose threat to the ‘non-target’ organisms, such as natural microbes and aquatic organisms. This review summarizes the recent research on (eco)toxicity of silver (Ag), CuO and ZnO NPs. Organism-wise it focuses on key test species used for the analysis of ecotoxicological hazard. For comparison, the toxic effects of studied NPs toward mammalian cells in vitro were addressed. Altogether 317 L(E)C50 or minimal inhibitory concentrations (MIC) values were obtained for algae, crustaceans, fish, bacteria, yeast, nematodes, protozoa and mammalian cell lines. As a rule, crustaceans, algae and fish proved most sensitive to the studied NPs. The median L(E)C50 values of Ag NPs, CuO NPs and ZnO NPs (mg/L) were 0.01, 2.1 and 2.3 for crustaceans; 0.36, 2.8 and 0.08 for algae; and 1.36, 100 and 3.0 for fish, respectively. Surprisingly, the NPs were less toxic to bacteria than to aquatic organisms: the median MIC values for bacteria were 7.1, 200 and 500 mg/L for Ag, CuO and ZnO NPs, respectively. In comparison, the respective median L(E)C50 values for mammalian cells were 11.3, 25 and 43 mg/L. Thus, the toxic range of all the three metal-containing NPs to target- and non-target organisms overlaps, indicating that the leaching of biocidal NPs from consumer products should be addressed. 相似文献
7.
To compare 0.5% centbucridine and 2% lignocaine (with adrenaline) as local anesthetic agents for dental treatment procedures in 12 to 14 y old children. A split mouth, triple blind randomised controlled trial design was adopted for this study. Fifty six children between 12 to 14 y of age requiring bilateral administration of inferior alveolar nerve block (IANB) were recruited for this study. The mandibular quadrants were randomly allotted to the drug being administered. Standardised protocol for local anesthesia administration was used. The primary outcomes assessed were onset, duration and depth of anesthesia using the pre-validated Visual Analog scale and effect on perioperative pulse rate using a pulse oximeter. There was no significant difference between centbucridine and lignocaine with respect to their mean onset [(105.181 and 99.727 s respectively), (p = 0.647)], duration of action [(91.931 and 91.613 min respectively), (p = 0.931)] and depth of anesthesia at 10, 30 and 60 min. Centbucridine showed a statistically significant drop in the pulse rate at 10 (p < 0.001) and 30 min (p < 0.001). There was no significant difference between 0.5% centbucridine and 2% lignocaine with respect to onset, duration and depth of anesthesia. 相似文献
8.
DepoFoam technology: a vehicle for controlled delivery of protein and peptide drugs. 总被引:12,自引:0,他引:12
Q Ye J Asherman M Stevenson E Brownson N V Katre 《Journal of controlled release》2000,64(1-3):155-166
A major challenge in the development of sustained-release formulations for protein and peptide drugs is to achieve high drug loading sufficient for prolonged therapeutic effect coupled with a high recovery of the protein/peptide. This challenge has been successfully met in the formulation of several peptide and protein drugs using the DepoFoam, multivesicular lipid-based drug delivery system. DepoFoam technology consists of novel multivesicular liposomes characterized by their unique structure of multiple non-concentric aqueous chambers surrounded by a network of lipid membranes. The objective of this paper is to demonstrate that DepoFoam technology can be used to develop sustained-release formulations of therapeutic proteins and peptides with high loading. DepoFoam formulations of a protein such as insulin, and peptides such as leuprolide, enkephalin and octreotide have been developed and characterized. The data show that these formulations have high drug loading, high encapsulation efficiency, low content of free drug in the suspension, little chemical change in the drug caused by the formulation process, narrow particle size distribution, and spherical particle morphology. Drug release assays conducted in vitro in biological suspending media such as human plasma indicate that these formulations provide sustained release of encapsulated drug over a period from a few days to several weeks, and that the rate of release can be modulated. In vivo pharmacodynamic studies in rats also show a sustained therapeutic effect over a prolonged period. These results demonstrate that the DepoFoam system is capable of efficiently encapsulating therapeutic proteins and peptides and effectively providing controlled delivery of these biologically active macromolecules. 相似文献
9.
Tarmo Jallai Katre Maasalu Tatjana Kums Jaan Ereline Helena Gapeyeva Mati Pääsuke 《Sport Sciences for Health》2017,13(1):93-98
Purpose
The aim of this study was to compare bone mineral density (BMD) in adolescent male basketball (BB) and soccer (S) players.Methods
The study included Estonian national youth league level participants: 12 BB (16.3 ± 0.7 years, 186.8 ± 6.6 cm, 80.9 ± 11.9 kg) and 15 S players (16.0 ± 0.3 years, 178.5 ± 8.1 cm, 66.3 ± 6.8 kg). All participants had a history of 7.9 ± 2.9 years of training, with training loads of 9.2 ± 1.8 h per week. Body composition and BMD were determined by dual X-ray absorptiometry (DXA).Results
BB were significantly taller, heavier and had greater lean body mass (LBM) compared to S. No significant (P < 0.05) differences existed in age, body fat %, sports participation, and weekly training load. BB had significantly (P < 0.05) greater BMD values in total body, lumbar spine, right arm, left arm, right leg, right femur, right femoral neck, and right femoral shaft compared to S. The biggest between-groups difference (P < 0.001) existed in upper extremities (25–28%). LBM was the main determinant for all BMD variables.Conclusions
Regular participation in basketball and soccer practice in adolescent males is associated with enhanced BMD in loaded sites specific to demands of the sport. Basketball practice seems to have higher impact on non-weight bearing bones, compared to soccer.10.