BACKGROUND: Demineralized bone matrix (DBM) is used for bone healing due to its osteoinductivity, but it requires a carrier for clinical application. Here, we report the effects on the osteoinductivity of DBM by use of a poloxamer 407-based hydrogel as the carrier, compared to sterile water. METHODS: DBM-W and DBM-H represent 27 wt% of DBM with sterile water and DBM with a poloxamer 407-based hydrogel, respectively. Both of the compositions were applied to human mesenchymal stem cell (MSC) cultures, and monitored for alkaline phosphatase (ALP) staining and ALP activity. Six 10-week-old athymic nude rats were used for abdominal muscle grafting with either DBM-W or DBM-H, and were tested by plane radiography, microfocus X-ray computed tomography (CT), and decalcified histology to evaluate ectopic bone formation. RESULTS: The DBM-W group showed stronger ALP staining at 7, 14, and 21 days of treatment, and significantly higher ALP activity at 7 and 14 days of treatment, compared to the DBM-H group. Plane radiography could not confirm the radio-opaque lesions in the rat ectopic bone formulation model. However, ectopic bone formation was observed in both groups by micro-CT. Compared to the DBM-H group, the DBM-W group showed higher bone volume, percent bone volume and trabecular number, and the difference in percent bone volume was statistically significant. Decalcified histology found bony tissue with lamellation in both groups. CONCLUSIONS: Our results suggest that poloxamer 407-based hydrogel has efficacy as a DBM carrier since it shows ectopic bone formation, but its effects on the quality and quantity of osteoblastic differentiation in rat abdominal ectopic bone and MSC are considered negative.
Animals ; Bone Matrix/*physiology ; Cell Culture Techniques ; Decalcification Technique ; Excipients/*pharmacology ; Hydrogels/pharmacology ; Male ; Mesenchymal Stromal Cells/*drug effects ; Osteogenesis/*drug effects ; Poloxamer/*pharmacology ; Rats ; Rats, Nude

P-glycoprotein (P-gp) located in the apicalmembranes of intestinal absorptive cells is an energy-dependent efflux pump which can reduce the bioavailability of a wide range of substrate drugs. There is increasingly interest in enhancing the bioavailability of these molecules by inhibiting intestinal P-gp. A classification of excipient inhibitors of intestinal P-gp nonionic surfactants, poly (ethylene glycol), derivates of beta-cyclodextrin and thiolated chitosan will be presented and then the inhibition mechanism will be discussed. Compared with traditional P-gp inhibitor, excipient inhibitors appear to have minimal nonspecific pharmacological activity, thus potential side effects can be mostly avoided. These excipient inhibitors, which hold the promise of replacing the traditional ones, will be extensively employed to significantly improve the intestinal absorption of poorly soluble and absorbed drugs as a result of P-gp inhibition, and thus to enhance the bioavailability of these drugs. However, the further studies of both the mechanism and clinical application are urgently needed.
ATP-Binding Cassette, Sub-Family B, Member 1 ; antagonists & inhibitors ; pharmacokinetics ; Animals ; Biological Availability ; Chitin ; analogs & derivatives ; pharmacology ; Excipients ; pharmacology ; Glycerol ; analogs & derivatives ; pharmacology ; Humans ; Intestinal Absorption ; drug effects ; Polyethylene Glycols ; pharmacology ; Surface-Active Agents ; pharmacology ; beta-Cyclodextrins ; pharmacology

Recently, chitosan has been widely used as a clarifier in clarification procedure for many kinds of TCM, which is better than alcohol in retaining active substances, such as polysaccharids, as well as the removal of heavy metals. Because it is a biocompatible polymer with low toxicity and can be biodegradable in vivo, chitosan with its derivatives is one of the ideal materials for drug controlled release systems to enhance the efficacy and reliability of TCM drug therapy. On the other hand, chitosan, the only natural alkalic polysaccharid, also has several therapeutic effects such as anti-bacteria, antipyrotic and ulcer healing. Chitosan and its derivatives wide application prosperity in pharmaceutical industry of Chinese medicine.
Animals ; Anti-Bacterial Agents ; pharmacology ; Biocompatible Materials ; Biodegradation, Environmental ; Chitosan ; analogs & derivatives ; chemistry ; toxicity ; Delayed-Action Preparations ; Drug Carriers ; Drug Compounding ; Drug Delivery Systems ; Excipients ; Humans

Environmental stimuli-sensitive biodegradable drug delivery systems are drawing more and more attentions because of their advantages such as smart properties, high efficiency and easy-to-handle properties. On the basis of a large quantity of references on this topic, a review has been made on the developments of the thermosensitive and pH-sensitive intelligent polymeric systems for drug delivery.
Biocompatible Materials ; chemistry ; pharmacology ; Biodegradation, Environmental ; Chitosan ; chemistry ; Delayed-Action Preparations ; Drug Delivery Systems ; Excipients ; chemistry ; Humans ; Polyethylene Glycols ; chemistry ; Polyglactin 910 ; chemistry

P-glycoprotein (P-gp) is an ATP-dependent multidrug efflux pump that acts as a major obstacle for oral drug delivery and cancer therapy. Recent reports have provided evidence that excipients often used in pharmaceutical formulations, such as Pluronic and TPGS, also have inhibitory effects on P-glycoprotein. Because inhibition of efflux transporters by polymeric inhibitors may dramatically increase the bioavailability of P-gp substrates with negligible side effects, identification of the mechanism and their structure activity relationship is therefore of significant importance for pharmaceutical development. Other than competitive inhibition for traditional inhibitors, polymeric inhibitors may modify P-gp function through alterations on membrane fluidity, inhibition of P-gp ATPase, depletion of intracellular ATP and down-regulating of P-gp expression. In the present review, the inhibition mechanism of potential polymeric inhibitors and their structure activity relationship will be discussed along with a brief introduction to the established methodologies.
ATP-Binding Cassette, Sub-Family B, Member 1 ; antagonists & inhibitors ; chemistry ; genetics ; metabolism ; Adenosine Triphosphatases ; metabolism ; Adenosine Triphosphate ; metabolism ; Animals ; Biological Availability ; Excipients ; pharmacology ; Gene Expression ; Humans ; Membrane Fluidity ; drug effects ; Polymers ; pharmacology ; Structure-Activity Relationship

To investigate the inhibitory effect of Pluronic on P-glycoprotein (P-gp) drug efflux pump, Caco-2 cells and animal models were established to study the influence of Pluronic on celiprolol transport across Caco-2 cell monolayer and intestinal mucous membrane with verapamil set as a positive control. Drug concentration was measured by HPLC and the apparent permeability coefficient (P(app)), absorption rate constant (k(a)) and the effective permeability coefficient (P(eff)) were calculated. P(app) of basolateral to apical side and apical to basolateral side was (2.10 +/- 0.13) x 10(-6) and (0.333 +/- 0.018) x 10(-6) cm x s(-1), respectively. Transports of celiprolol across Caco-2 cell monolayer were influenced by both verapamil and Pluronic. The absorption constants (k(a)) of celiprolol at duodenum, jejunum, ileum, and colon were (0.09 +/- 0.03), (0.14 +/- 0.04), (0.11 +/- 0.03) and (0.05 +/- 0.02) h(-1), k(a) of celiprolol in verapamil group were (0.14 +/- 0.03), (0.24 +/- 0.02), (0.25 +/- 0.03) and (0.23 +/- 0.02) h(-1), and k(a) of celiprolol in Pluronic group were (0.13 +/- 0.02), (0.22 +/- 0.02), (0.22 +/- 0.03) and (0.20 +/- 0.03) h(-1), respectively. Pluronic showed significant effect on inhibiting P-gp of Caco-2 cell and intestinal mucosa in rats.
ATP-Binding Cassette, Sub-Family B, Member 1 ; metabolism ; Animals ; Biological Transport ; drug effects ; Caco-2 Cells ; Celiprolol ; pharmacokinetics ; Excipients ; Humans ; Intestinal Absorption ; drug effects ; Intestinal Mucosa ; metabolism ; Jejunum ; metabolism ; Male ; Permeability ; Poloxamer ; administration & dosage ; pharmacology ; Rats ; Rats, Sprague-Dawley

This study demonstrates that prophylactic effect of plaster and cataplasm contained ketoprofen in adjuvant arthritis therapy by X-ray. Adjuvant arthritis was induced by a single injection of Freund's complete adjuvant. Mature female Sprague-Dawley rats were designated to 3 groups such as nontreated control, plaster-treated (PT) and cataplasm-treated (CT), each of which was composed of ten animals. The PT and the CT groups showed reduced primary paw swelling, but secondary paw swelling was not affected. Bony changes were observed in all regions of the femur and tibia of the nonadjuvant-injected leg and the adjuvant-injected leg. The mean radiographic scores of the PT and the CT groups were significantly lower than those of the control group from day 0 to 7 of the experimental period (p<0.05, p<0.01). The CT rats showed reduced poly-arthritis development than the PT rats. Our results suggest that radiographic assessment of bony changes is more suitable for measuring changes in long bones such as femur or tibia than in vertebrae. The prophylactic effect of CT prominently suppressed edematous swelling and bony changes in arthritic limb compared with PT.
Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology ; Arthritis, Experimental/*prevention & control ; Calcium Sulfate ; Drug Carriers/administration & dosage ; Excipients/*administration & dosage ; Female ; Freund's Adjuvant ; Ketoprofen/*administration & dosage/analogs & derivatives/therapeutic use ; Rats ; Rats, Sprague-Dawley

Drug delivery system (DDS) is a novel approach to overcome multidrug resistance (MDR) in tumors nowadays. This work was designed to investigate a new micellar delivery system for in vitro reversal of resistant ovarian tumor cells, based on a nonionic triblock copolymer Pluronic P105 and paclitaxel (PTX). The PTX-loaded polymeric micelles (P105/PTX) were prepared by thin film-hydration methods. Based on the results of single factor experiments, the P105/PTX micelle formulation was optimized by employing the central composite design-response surface methodology. The physico-chemical properties of the P105/PTX micelles were characterized, including micelle size, drug loading coefficient, in vitro release behavior, etc. The cytotoxicity of the P105/PTX micelles was assessed against human ovarian tumor cell line, SKOV-3/PTX, by a standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl (MTT) assay. In order to understand the possible mechanism of Pluronic effects in resistant tumor cells, cellular uptake study of micellar PTX or Rhodamine-123 (R-123) was also carried out. The results showed that the micelle size was about 24 nm with drug loading coefficient of 1.1% and PTX concentration of 700 microg x mL(-1). The cumulative release amount of PTX from the P105/PTX micelles was only 45.4% in 6 h (P < 0.05) and 79.6% in 24 h, whereas Taxol injection in 6 h released 95.2% PTX. The IC50 values of the P105/PTX micelles and Taxol injection against SKOV-3/PTX were 1.14 and 5.11 microg x mL(-1), and resistance reversion index (RRI) was 9.65 and 2.15, respectively. The micellar PTX or R-123 exhibited a significant increase in cellular uptake in resistant SKOV-3/PTX cells compared with free PTX or R-123. These results indicated that PTX could effectively be solubilized by Pluronic P105 block copolymers via thin film-hydration process and formulation optimization, producing nano-scale polymeric micelles with sustained release property in vitro. The P105/PTX micelles were effectively able to reverse resistance to PTX in SKOV-3/PTX tumor cells compared with Taxol injection or free PTX solution, and the enhanced cytotoxicity in the resistant SKOV-3/PTX cell was related to the improved cellular uptake of PTX by Pluronic P105 copolymers.
Antineoplastic Agents, Phytogenic ; administration & dosage ; chemistry ; pharmacology ; Cell Line, Tumor ; Drug Carriers ; Drug Delivery Systems ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Excipients ; chemistry ; Female ; Humans ; Inhibitory Concentration 50 ; Micelles ; Ovarian Neoplasms ; metabolism ; pathology ; Paclitaxel ; administration & dosage ; chemistry ; metabolism ; pharmacology ; Particle Size ; Poloxamer ; chemistry

Poloxamers are found to be an efficient adjuvant with multiple effects and are applied generally in pharmaceutical field. In recent years, it is investigated that poloxamers can increase the permeability of a broad spectrum of drugs through blood-brain barrier (BBB) by means of manifold mechanisms included: (1) inhibiting P-glycoprotein and multidrug-resistance associated protein efflux systems on BBB; (2) adsorbing different apolipoproteins in plasma on the surface of poloxamer-coated nanoparticles, which could interact with BBB through different receptors and mechanisms; (3) connecting to specific ligands and monoclonal antibodies to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium. Significant roles of poloxamer in drug transport across BBB are considered in this review which provides for important guidance to the design of brain-targeted drug delivery system.
ATP Binding Cassette Transporter, Sub-Family B ; antagonists & inhibitors ; metabolism ; ATP Binding Cassette Transporter, Sub-Family G, Member 2 ; ATP-Binding Cassette Transporters ; antagonists & inhibitors ; metabolism ; Animals ; Blood-Brain Barrier ; drug effects ; metabolism ; Brain ; metabolism ; Drug Carriers ; Drug Delivery Systems ; Excipients ; pharmacology ; Glucose Transport Proteins, Facilitative ; antagonists & inhibitors ; metabolism ; Humans ; Monocarboxylic Acid Transporters ; antagonists & inhibitors ; metabolism ; Multidrug Resistance-Associated Proteins ; antagonists & inhibitors ; metabolism ; Nanoparticles ; Permeability ; Poloxamer ; chemistry ; pharmacology