Pharmacokinetics and Pharmacodynamics of a Depolymerized Glycosaminoglycan from Holothuria fuscopunctata, a Novel Anticoagulant Candidate, in Rats by Bioanalytical Methods.

dHG-5 (Mw 5.3 kD) is a depolymerized glycosaminoglycan from sea cucumber Holothuria fuscopunctata. As a selective inhibitor of intrinsic Xase (iXase), preclinical study showed it was a promising anticoagulant candidate without obvious bleeding risk. In this work, two bioanalytical methods based on the anti-iXase and activated partial thromboplastin time (APTT) prolongation activities were established and validated to determine dHG-5 concentrations in plasma and urine samples. After single subcutaneous administration of dHG-5 at 5, 9, and 16.2 mg/kg to rats, the time to peak concentration (Tmax) was at about 1 h, and the peak concentration (Cmax) was 2.70, 6.50, and 10.11 µg/mL, respectively. The plasma elimination half-life(T1/2ß) was also about 1 h and dHG-5 could be almost completely absorbed after s.c. administration. Additionally, the pharmacodynamics of dHG-5 was positively correlated with its pharmacokinetics, as determined by rat plasma APTT and anti-iXase method, respectively. dHG-5 was mainly excreted by urine as the unchanged parent drug and about 60% was excreted within 48 h. The results suggested that dHG-5 could be almost completely absorbed after subcutaneous injection and the pharmacokinetics of dHG-5 are predictable. Studying pharmacokinetics of dHG-5 could provide valuable information for future clinical studies.

Silk-elastinlike protein polymers enhance the efficacy of a therapeutic glycosaminoglycan for prophylactic treatment of radiation-induced proctitis.

Radiation-induced proctitis (RIP) is the most common clinical adverse effect for patients receiving radiotherapy as part of the standard course of treatment for ovarian, prostate, colon, and bladder cancers. RIP limits radiation dosage, interrupts treatment, and lowers patients' quality of life. A prophylactic treatment that protects the gastrointestinal tract from deleterious effects of radiotherapy will significantly improve patient quality of life and may allow for higher and more regular doses of radiation therapy. Semi-synthetic glycosaminoglycan (GAG), generated from the sulfation of hyaluronic acid, are anti-inflammatory but have difficulty achieving therapeutic levels in many tissues. To enhance the delivery of GAG, we created an in situ gelling rectal delivery system using silk-elastinlike protein polymers (SELPs). Using solutions of SELP 815K (which contains 6 repeats of blocks comprised of 8 silk-like units, 15 elastin-like units, and 1 lysine-substituted elastin-like unit) with GAG GM-0111, we created an injectable delivery platform that transitioned in <5min from a liquid at room temperature to a hydrogel at body temperature. The hydrogels released 50% of their payload within 30min and enhanced the accumulation of GAG in the rectum compared to traditional enema-based delivery. Using a murine model of radiation-induced proctitis, the prophylactic delivery of a single dose of GAG from a SELP matrix administered prior to irradiation significantly reduced radiation-induced pain after 3, 7, and 21days by 53±4%, 47±10%, and 12±6%, respectively. Matrix-mediated delivery of GAG by SELP represents an innovative method for more effective treatment of RIP and promises to improve quality of life of cancer patients by allowing higher radiotherapy doses with improved safety.

Pharmacological profile of sulodexide.

Since its introduction, sulodexide has been used on and off for several indications. More recently this agent has become revitalized and tested in newer indications. Sulodexide is composed of glycosaminoglycan that includes a mixture of fast-moving heparin and dermatan sulfate. It exerts its anticoagulant and antithrombotic action through interactions with both AT and HCII. Sulodexide has been proven to have effects on the fibrinolytic system, platelets, endothelial cells, inflammation and more recently metalloproteases. The administration of sulodexide results in the release of lipoprotein lipase and has been shown to reduce the circulating level of lipids. It has also shown to decrease the viscosity of both whole blood and plasma. Sulodexide differs from heparin in its oral bioavailability and longer half-life. There is also less bleeding associated with sulodexide. In addition, oral administration of sulodexide does not interfere with the pharmacologic actions of commonly used agents. Similar to heparin, sulodexide releases TFPI which contributes to its antithrombotic effect and anti-inflammatory properties. Sulodexide has been proven to be effective in peripheral arterial thrombosis and venous thrombosis. It is also clinically active in the treatment of venous leg ulcers and intermittent claudication. More recent data suggest that sulodexide can be used in tinnitus and in vascular vertigo. Additional studies in these indications are required. Sulodexide was generally safe and well tolerated in the clinical trials, without any severe bleeding complications. Therefore sulodexide appears to be a good treatment for all arterial and venous diseases and for the prevention of progression of disease.

Development of a surface to increase retinal pigment epithelial cell (ARPE-19) proliferation under reduced serum conditions.

Age related macular degeneration of the eye is brought about by damage to the retinal pigment epithelium (RPE) and is a major cause of adult blindness. One potential treatment method is transplantation of RPE cells grown in vitro. Maintaining RPE cell viability and physiological function in vitro is a challenge, and this must also be achieved using materials that can be subsequently used to deliver an intact cell sheet into the eye. In this paper, plasma polymerisation has been used to develop a chemically modified surface for maintaining RPE cells in vitro. Multiwell plates modified with a plasma copolymer of allylamine and octadiene maintained RPE cell growth at a level similar to that of TCPS. However, the addition of bound glycosaminoglycans (GAGs) to the plasma polymerised surface significantly enhanced RPE proliferation. Simply adding GAG to the culture media had no positive effect. It is shown that a combination of plasma polymer and GAG is a promising method for developing suitable surfaces for cell growth and delivery, that can be applied to any substrate material.

Development and use of sulodexide in vascular diseases: implications for treatment.

Sulodexide (SDX), a sulfated polysaccharide complex extracted from porcine intestinal mucosa, is a blend of two glycosaminoglycan (GAG) entities, namely a fast-moving heparin (HP) fraction and a dermatan sulfate (DS; 20%) component. The compound is unique among HP-like substances in that it is biologically active by both the parenteral and oral routes. A main feature of the agent is to undergo extensive absorption by the vascular endothelium. For this reason, in preclinical studies, SDX administered parenterally displays an antithrombotic action similar to that of HPs but associated with fewer alterations of the blood clotting mechanisms and tests, thus being much less conducive to bleeding risk than HPs. When given orally, SDX is associated with minimal changes in classic coagulation tests, but maintains a number of important effects on the structure and function of endothelial cells (EC), and the intercellular matrix. These activities include prevention or restoration of the integrity and permeability of EC, counteraction versus chemical, toxic or metabolic EC injury, regulation of EC-blood cell interactions, inhibition of microvascular inflammatory and proliferative changes, and other similar effects, thus allowing oral SDX to be considered as an endothelial-protecting agent. The best available clinical evidence of the efficacy of SDX administered orally with or without an initial parenteral phase is the following: alleviation of symptoms in chronic venous disease and especially acceleration of healing of venous leg ulcers; prevention of cardiovascular events in survivors after acute myocardial infarction; marked improvement of intermittent claudication in patients with peripheral occlusive arterial disease; and abatement of proteinuria in patients with diabetic nephropathy that may contribute to the amelioration or stabilization of kidney function. Although further clinical trials are warranted, SDX is presently widely accepted in many countries as an effective and safe long-term, endothelial-protecting drug.

Glycosaminoglycan-binding hydrogels enable mechanical control of human pluripotent stem cell self-renewal.

Reaping the promise of human embryonic stem (hES) cells hinges on effective defined culture conditions. Efforts to identify chemically defined environments for hES cell propagation would benefit from understanding the relevant functional properties of the substratum. Biological materials are often employed as substrata, but their complexity obscures a molecular level analysis of their relevant attributes. Because the properties of hydrogels can be tuned and altered systematically, these materials can reveal the impact of substratum features on cell fate decisions. By tailoring the peptide displayed to cells and the substrate mechanical properties, a hydrogel was generated that binds hES cell surface glycosaminoglycans (GAGs) and functions robustly in a defined culture medium to support long-term hES cell self-renewal. A key attribute of the successful GAG-binding hydrogels is their stiffness. Only stiff substrates maintain hES cell proliferation and pluripotency. These findings indicate that cells can respond to mechanical information transmitted via GAG engagement. Additionally, we found that the stiff matrices afforded activation of the paralogous proteins YAP/TAZ, which are transcriptional coactivators implicated in mechanosensing and hES cell pluripotency. These results indicate that the substratum mechanics can be tuned to activate specific pathways linked to pluripotency. Because several different hES and induced pluripotent stem cell lines respond similarly, we conclude that stiff substrata are more effective for the long-term propagation of human pluripotent stem cells.

Dermal absorption of mucopolysaccharide polysulfate (heparinoid) in human and minipig.

Dermal absorption of mucopolysaccharide polysulfate (MPS, the active ingredient of Hirudoid") in human and minipig was investigated by using 14C-labeled MPS. Three types of human and minipig skin samples were used: intact, dried and tape-stripped. At 24 h after application of 14C-MPS to intact human skin on a Franz cell in vitro, the radioactivity was detected in 0.98, 1.34, and 0.08% of the applied dose in stratum corneum, epidermal-dermal skin, and receptor fluid, respectively. In dried human skin, the amount of radioactivity detected was similar to that in intact human skin. By contrast, in tape-stripped human skin, higher radioactivity was detected in epidermal-dermal skin and receptor fluid (2.85 and 0.33% of the applied dose, respectively) than in intact or dried skin. Minipig skin showed 1.5 to 4.5 times greater dermal absorption of 14C-MPS, as compared with human skin. In an in vivo study with minipig, radioactivity was detected at the dosing skin site after dermal administration of 14C-MPS. The stability of 14C-MPS in human skin after dermal application was evaluated by agarose gel electrophoresis and ion-exchange chromatography. It was suggested that 14C-MPS absorbed into human skin would be stable because the chromatogram behaviors of the radioactivity on the two types of method were not shifted. Microautoradiography of human and minipig skins after 14C-MPS dosing showed that radioactivity was widely distributed in the epidermis in the area near hair follicles. The present results clearly demonstrate that MPS is stable and that a small fraction of it is percutaneously absorbed by human and minipig skin.

Absorption and tissue distribution of a novel carboxymethyldextran after oral administration.

The aim of this study was to investigate the development of an oral dextran derivative OTR4120. Pharmacokinetics (PK) parameters of OTR4120 were determined after treatment with intravenous injection (i.v.) at dose 5 mg/kg, intraperitoneal injection (i.p.) at dose 50 mg/kg or oral administration at dose 70 mg/kg. To study distribution at dose 70 mg/kg after oral administration, OTR4120 was given by gavage to mice. In ex vivo experiments, SDS-PAGE showed that plasma of mice treated orally at dose 70 mg/kg induced the formation of covalently linked complexes between antithrombin III and thrombin. OTR4120 were absorbed and metabolized following oral administration. OTR4120 given i.v., i.p. and oral had relatively small volume of distribution 0.95 L/kg and 4.68 L/kg respectively, plasma clearance was 45, 520 and 514 ml/h per kg after i.v., i.p. or oral administration respectively. Short elimination half-life was 80 min after i.p. administration and 383 min after oral administration. OTR4120 was distributed in the spleen and kidney and accumulated there over a long period, whereas the OTR4120 levels in liver were negligible a 24 hours after oral administration. Food do not change the oral bioavailability of OTR4120 in mice, AUC, C(max) and T(max) of OTR4120 were not significantly different when mice received the oral dose with food compared with under fasting conditions. This work presents another therapeutic agents administration way using dextran delivery system.

Attenuation of tumor growth by formation of antiproliferative glycosaminoglycans correlates with low acetylation of histone H3.

Glycosaminoglycan (GAG) chains anchored to core proteins form proteoglycans, widely distributed cell-surface macromolecules with multiple functions, such as regulation of growth factor and cytokine signaling, cell-cell interactions, and uptake of biomolecules. The biosynthesis of GAG can be manipulated by xylosides attached to various hydrophobic groups, and we have earlier reported that a naphthoxyloside, 2-(6-hydroxynaphthyl) beta-D-xylopyranoside (XylNapOH), which serves as a primer for GAG synthesis, reduces tumor load up to 97% in vivo, despite lower efficiency in vitro. Here we show, using radiolabeled xylosides and coculture experiments, that XylNapOH-treated bladder and breast carcinoma cells secrete antiproliferative GAG chains that are taken up by both normal and cancer cells and transported to the cell nuclei where they induce an antiproliferative effect, accompanied by apoptosis. We also show that XylNapOH treatment lowers the level of histone H3 acetylation selectively in bladder and breast carcinoma cells without affecting expression of histone H3. However, XylNapOH-primed GAG chains from normal cells are not internalized and do not cause growth retardation. Using in vitro and in vivo C6 glioma cell and tumor models, we show that XylNapOH is much more effective in vivo than in vitro. We propose that, in vivo, the antiproliferative XylNapOH-primed GAG chains produced by tumor cells inhibit tumor growth in an autocrine fashion by formation of antiproliferative GAG chains on the xyloside prodrug, whereas no antiproliferative GAG chains are produced by surrounding normal cells. This is a novel mechanism for targeting tumor cells, making these xylosides promising drug candidates for antitumor therapy.

Importance of pharmaceutical composition and evidence from clinical trials and pharmacological studies in determining effectiveness of chondroitin sulphate and other glycosaminoglycans: a critique.

OBJECTIVES: Chondroitin sulphate (CS) has attracted much interest over the past two decades or so as a biological agent for use in the relief of pain and joint symptoms in osteoarthritis. Earlier clinical investigations produced variable, if encouraging results. This variability was partly due to limitations on the study designs and the lack of availability of standardized CS. Recently, high quality and fully standardized CS (Condrosulf) has become available and its effects have been studied in large-scale osteoarthritis trials, which are discussed here. KEY FINDINGS: There is now evidence for symptom- and structure-modifying (radiologically-observed) effects. These studies show that CS (a) has slow onset of response and that relief of pain may not be like that of the direct analgesic actions of non-steroidal anti-inflammatory drugs (NSAIDs), (b) there are indications of reduced need for intake of analgesics (e.g. NSAIDs) in patients taking CS, and (c) quality of life and cost-benefits may be associated with use of CS. Safety evaluations show that the incidence of adverse reactions is low. Pharmacokinetic studies indicate that although oral absorption is relatively fast CS has moderate oral bioavailability (15-24%) and that depolymerised and degraded CS that is evident after absorption, together with CS itself, may take some time to accumulate in target joints. The pharmacodynamic actions of CS indicate that it has anti-inflammatory effects that include multiple actions involving reduction of catabolic reactions and enhanced anabolic (proteoglycan) synthetic reactions in cartilage and may block osteoclast activation in bone. Further studies are required to (a) establish the effects of depolymerised and degraded CS on degradation of cartilage and bone in vitro, and (b) MRI and other investigations of the effects in osteoarthritis of long-term CS treatment. SUMMARY: The findings from this review show there may be potential value of CS in reducing the dependence on intake of NSAIDs and analgesics in patients with osteoarthritis, while at the same time having favourable safety.

Formulations and delivery vehicles for bone morphogenetic proteins: latest advances and future directions.

Growth factors are essential components of the diamond concept model. The bone morphogenetic proteins (BMPs) are the most potent and promising growth factors and their clinical efficacy is well demonstrated for specific indications. Application of BMPs involves a carrier material to enhance local residual time and pharmacokinetics. On the other hand carrier materials, collagen at this point, also limit the use of BMPs, for example in minimally invasive application methods. In this overview, the pharmacokinetics of BMPs, and various carrier materials (collagen, synthetic polymers, calcium phosphates, hyaluronic acid, CMC, and sodium acetate) are discussed. No other carrier material than collagen has been proven effective in clinical studies. Other formulations are needed to improve the residual time and handling.

Preclinical evaluation of technetium 99m-labeled P1827DS for infection imaging and comparison with technetium 99m IL-8.

BACKGROUND: The technetium 99 m (99mTc)-radiolabeled, leukocyte-avid peptide-glycoseaminoglycan complex, [99mTc]P1827DS, has been synthesized as an improved infection/inflammation imaging agent to [99mTc]P483H (LeukoTect, Diatide). In a phase I/II clinical trail, [99mTc]P483H images were equivalent to those obtained with 111In ex vivo labeled leukocytes. However, there was physiologic accumulation of radioactivity in the body that could hamper interpretation of the images. In this study, the potential of [99mTc]P1827DS for infection imaging was assessed in comparison with [99mTc]P483H and the well-described imaging agent [99mTc] hydrazinonicotinamide (HYNIC)-interleukin 8 (IL-8). METHODS: The binding of [99mTc]P1827DS to human blood cell was studied in vitro. A rabbit Escherichia coli infection model was used to perform the biodistribution and imaging studies with [99mTc]P1827DS, [99mTc]P483H and [99mTc]HYNIC-IL-8. RESULTS: [99mTc]P1827DS binds to leukocytes but not to erythrocytes. The leukocyte binding was not saturable up to an investigated concentration of 10 microM. The accumulation of [99mTc]P1827/DS at the infection site strongly depends on the P1827/DS ratio and was optimal at a molar ratio of 10:1. [99mTc]P1827DS shows improved biodistribution over [99mTc]P483H with similar uptake at the infection site. Abscess uptake of [99mTc]HYNIC-IL-8 was approximately three times higher than that of [99mTc]P1827DS. [99mTc]HYNIC-IL-8 showed high accumulation in the kidneys, whereas [99mTc]P1827DS showed high lung uptake and slightly higher accumulation in the liver and spleen. CONCLUSION: [99mTc]P1827DS is a potential new inflammation imaging agent, which clearly visualized the abscess in the rabbit E. coli infection model and showed improved biodistribution compared to [99mTc]P483H. However, the infection uptake and biodistribution of [99mTc]P1827DS is not superior to that of [99mTc]HYNIC-IL-8 in this animal model.

[Polymer and oligomer based doxorubicin carriers]. / Polimerowe i oligomerowe nosniki doksorubicyny.

Doxorubicin and other anthracycline derivatives play an important role in the treatment of many malignant diseases. Unfortunately, clinical effectiveness of this class of drugs is limited by cumulative cardiotoxicity which occurs in significant percentage of patients at cumulative dose in the range 450-600 mg/m2. Therefore, several strategies have been developed to reduce cardiotoxicity of doxorubicin and its analogues. One of the possible ways leading to the improvement of anticancer selectivity of doxorubicin is the design of polymer and olygomer carriers which may transport drug molecules more efficiently and more specifically. Synthetic polymers are of increasing interest as therapeutic agents owing to their enhanced pharmacokinetic profiles relative to small molecule drugs. Currently a new class of multifunctional polymers is being prepared that can "mask" biologically active compounds, such as cytotoxic agents, until they reach target sites, but which can then release the agent in situ to effect the therapy. The legitimacy of the development of polymer based doxorubicine carriers is supported by the growing number of clinical reports indicating that the use of hydrophilic polymers or polymer coated liposomes as a platform for delivery of the drug results in better therapeutic effects than the free drug. In this article we present the most promising strategies directed at the development of improved anthracycline drugs formulations based of polymer and olygomer carriers. We review: 1) polyethylenoglycol-coated ("pegylated") liposomal doxorubicin; 2) extracellulary tumor-activated prodrugs which are conjugates of doxorubicin with peptides; 3) doxorubicin coated by higly polymerised glycosoaminoglycans; 4) conjugates of doxorubicin with copolymer of N-(2-hydroxypropyl)methacrylamide.

Reduced urinary excretion of sulfated polysaccharides in diabetic rats.

The aim of the present study was to further understand the changes in renal filtration that occur in the early stages of diabetes mellitus. Diabetes was induced in male Wistar rats by a single injection of streptozotocin. Glycemia, body weight, 24-h urine volume and urinary excretion of creatinine, protein and glycosaminoglycans were measured 10 and 30 days after diabetes induction. All the diabetic animals used in the present study were hyperglycemic, did not gain weight, and presented proteinuria and creatinine hyperfiltration. In contrast, the glycosaminoglycan excretion decreased. Dextran sulfates of different molecular weights (6.0 to 11.5 kDa) were administered to the diabetic rats, and to age-matched, sham-treated controls. Most of the dextran sulfate was excreted during the first 24 h, and the amounts excreted in the urine were inversely proportional to the dextran sulfate molecular weight for all groups. Nevertheless, diabetic rats excreted less and accumulated more dextran sulfate in kidney and liver, as compared to controls. These differences, which were observed only for the dextran sulfates of higher molecular weights (>7 kDa), increased with the duration of diabetes. Our findings suggest differential renal processing mechanisms for proteins and sulfated polysaccharides, with the possible involvement of kidney cells.

Exogenous glycosaminoglycans coat damaged bladder surfaces in experimentally damaged mouse bladder.

BACKGROUND: Interstital cystitis is often treated with exogenous glycosaminoglycans such as heparin, chondroitin sulphate (Uracyst), hyaluronate (Cystistat) or the semi-synthetic pentosan polysulphate (Elmiron). The mechanism of action is presumed to be due to a coating of the bladder surface to replace the normally present chondroitin sulphate and heparan sulphate lost as a result of the disease. This study used fluorescent labelled chondroitin sulphate to track the distribution of glycosaminoglycans administered intravesically to mouse bladder that had been damaged on the surface. METHODS: The surfaces of mouse bladders were damaged by 3 mechanisms -- trypsin, 10 mM HCl, and protamine sulphate. Texas Red-labeled chondroitin sulphate was instilled into the bladders of animals with damaged bladders and controls instilled only with saline. Bladders were harvested, frozen, and sectioned for examination by fluorescence. RESULTS: The normal mouse bladder bound a very thin layer of the labelled chondroitin sulphate on the luminal surface. Trypsin- and HCl-damaged bladders bound the labelled chondroitin sulphate extensively on the surface with little penetration into the bladder muscle. Protamine produced less overt damage, and much less labelling was seen, presumably due to loss of the label as it complexed with the protamine intercalated into the bladder surface. CONCLUSION: Glycosaminoglycan administered intravesically does bind to damaged bladder. Given that the changes seen following bladder damage resemble those seen naturally in interstitial cystitis, the mechanisms proposed for the action of these agents is consistent with a coating of damaged bladder.

Low-molecular-weight heparin and dermatan sulfate end group-labeled with tyramine and fluorescein. Biochemical and biological characterization of the fluorescent-labeled heparin derivative.

To improve the understanding of the biological functions and pharmacology of heparin and dermatan sulfate, low-molecular-weight heparin (LMWH) and low-molecular-weight dermatan sulfate (LMWDS) were labeled with tyramine (T) by covalently linking T to the terminal residue of 2,5-anhydromannose (or 2,5-anhydrotalose for dermatan sulfate). The covalent labeling was demonstrated by nuclear magnetic resonance spectroscopy. The tyramine-labeled LMWH (LMWH-T) was also labeled with fluorescein (F) by further reacting it with fluorescein isothiocyanate. The fluoresceinated LMWH-T (LMWH-T,F ) was used to analyze biological functions on blood coagulation and binding to leukocytes. The biological activities on factor Xa and thrombin inhibition remained unchanged compared with the parent compound. Flow cytometric analysis of leukocytes demonstrated binding of the modified heparin to granulocytes, monocytes, and lymphocytes, the half-live being twice as long as the antifactor Xa activity. F-labeled heparin was displaced by unlabeled heparin from all three populations of leukocytes. Binding of heparin to leukocytes may play an important role in inflammation and atherosclerosis.

Retention of oxidized LDL by extracellular matrix proteoglycans leads to its uptake by macrophages: an alternative approach to study lipoproteins cellular uptake.

Interaction between arterial macrophages and oxidized LDL (Ox-LDL) leads to foam cell formation, a critical step during early atherogenesis. Until now, cellular uptake of lipoproteins was studied through incubation of the media-soluble lipoprotein with cultured macrophages. However, as lipoproteins in the arterial wall are bound to subendothelial matrix, we questioned whether the retention (binding) of Ox-LDL to a macrophage-derived extracellular matrix (ECM) could lead to enhanced uptake by macrophages. The uptake of ECM-bound Ox-LDL by activated macrophages (by phorbol myristate acetate) was lipoprotein dose dependent, time dependent and higher (by 1.5-fold) than the uptake of ECM-bound native LDL. Preincubation of the ECM with lipoprotein lipase before the addition of Ox-LDL was essential for the uptake of ECM-bound Ox-LDL by the macrophages. After radiolabeling of the ECM glycosaminoglycans (GAGs), we found that ECM-bound Ox-LDL is taken up by the macrophages together with the ECM-GAG. Finally, these results were further confirmed through the use of ECM obtained from mouse peritoneal macrophages (MPMs), derived from atherosclerotic, apoE-deficient mice. In 24-week-old mice with developed atherosclerosis, the GAG content of their MPM-derived ECM increased by 52%, the ability of their MPM-derived ECM to bind Ox-LDL increased by 57%, and macrophage uptake of Ox-LDL that was retained by the MPM-derived ECM increased by 86%. In conclusion, the present study demonstrated that ECM-bound Ox-LDL is taken up by activated macrophages. This may represent a physiopathological phenomenon that leads to cholesterol and oxysterol accumulation in arterial macrophages, the hallmark of early atherosclerosis.

Effect of a novel mucoadhesive polysaccharide obtained from tamarind seeds on the intraocular penetration of gentamicin and ofloxacin in rabbits.

This report describes the efficacy of a novel mucoadhesive polymer, the tamarind seed polysaccharide, as a delivery system for the ocular administration of hydrophilic and hydrophobic antibiotics. Healthy rabbits were subjected to repeated ocular instillations with either conventional gentamicin or ofloxacin or these agents viscosified with the tamarind seed polysaccharide. Administration of viscosified preparations produced antibiotic concentrations both in the aqueous humour and cornea that were significantly higher than those achieved with the drugs alone. The increased drug absorption and the prolonged drug elimination phase obtained with the viscosified formulations indicate the usefulness of the tamarind seed polysaccharide as an ophthalmic delivery system for topical administration of antibiotics.

Uptake and distribution of tritium-labeled polysulfated glycosaminoglycan in serum, urine, and superficial digital flexor tendon of rabbits after intramuscular administration.

OBJECTIVE: To determine concentrations of tritiated polysulfated glycosaminoglycans (3H-PSGAG) in serum, urine, and the superficial digital flexor tendon (SDFT) of rabbits after IM administration and molecular weight of 3H-PSGAG recovered from the SDFT. ANIMALS: Twenty-five 12-week-old New Zealand White rabbits. PROCEDURE: Rabbits were given a single dose of 3H-PSGAG (1.1 mg/kg [70 mCi of specific activity/kg] of body weight) IM. At each of 5 sample times (2, 24, 48, 96, and 192 hours), 5 rabbits were randomly selected and sedated, and blood and urine samples were collected. Rabbits were then euthanatized, and the SDFT were immediately harvested from the hind limbs. Scintillation spectrometry was used to detect concentration of 3H-PSGAG in fluid and tissue samples. Gel-filtration chromatography was used to determine molecular weight of recovered 3H-PSGAG. RESULTS: Mean concentrations of 3H-PSGAG in SDFT, serum, and urine were greatest 2 hours after administration. Tritiated PSGAG could be detected in all samples collected 192 hours after administration. Gel-filtration chromatography confirmed that 3H-PSGAG detected in SDFT samples was high molecular weight PSGAG. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicate that PSGAG is distributed to the SDFT, serum, and urine after IM administration in rabbits. Further study is needed to determine whether the same is true in horses and to determine what effect, if any, PSGAG has on inflammation of the SDFT.