Dextrin-based nanomagnetogel: in vivo biodistribution and stability.

The biodistribution profile of a new dextrin nanomagnetogel, which consists of γ-Fe2O3 superparamagnetic nanoparticles loaded within a polymeric matrix of modified dextrin, was studied in mice. The nanomagnetogel bear a monomodal size distribution profile (average diameter 110 nm) close to neutral surface charge and higher relaxivity (r2 = 215-248 mM(-1) s(-1) and r2/r1 = 13-11) than those of commercial formulations (r2 = 160-177 mM(-1) s(-1) and r2/r1 = 4-7). Also, the observed blood half-life-approximately 4 h-is superior to that of similar commercially available formulations, which remain for a few minutes in circulation. PEGylation resulted in 1.7- and 1.2-fold lower accumulation in the liver and spleen, respectively, within the first 24 h. Noteworthy, a good correlation was obtained between the amount of polymer (quantified by scintigraphy) in the spleen, 48 h after administration, and the amount of iron physically loaded through hydrophobic interactions (quantified by ICP) indicating the absence of iron leakage from the polymeric matrix. This study provides evidence of the in vivo stability of a self-assembled nanomagnetogel, a relevant feature which is seldom reported in the literature.

Safety profile of dextran-spermine gene delivery vector in mouse lungs.

A nano-sized polymer, dextran-spermine (D-SPM), was shown to have the capacity to deliver gene to the lung of mouse via intranasal route. In this study, assessments on the safety profile of D-SPM were performed to complement the gene expression results. African green monkey kidney fibroblast (COS-7) and human adenocarcinoma breast (MCF-7) cells transfected with D-SPM/pDNA showed massive reduction in the number of viable cells. As for in vivo study, elevated level of neutrophils was observed, despite the minimal level of pro-inflammatory cytokines (TNF-alpha, IL-12, IFN-gamma) detected in the bronchoalveolar lavage fluid (BALF) of mice treated with the D-SPM/pDNA complexes. Histology profile examinations of the lungs showed mild inflammatory responses, with inflamed areas overlap with healthy areas. Although reduction of mice weight was seen at day 1 post administration, the mice did not show any sign of abnormal behavior or physical appearance. Biodistribution study was performed to determine the ability of the D-SPM/pDNA complexes to infiltrate to other non-intended organs. The result showed that the D-SPM/pDNA complexes were only localized at the lung and no gene expression was detected in other organs or blood. In short, these results indicate that the D-SPM/pDNA exhibited mild toxicity in the mouse lungs.

Studies on the biodistribution of dextrin nanoparticles.

The characterization of biodistribution is a central requirement in the development of biomedical applications based on the use of nanoparticles, in particular for controlled drug delivery. The blood circulation time, organ biodistribution and rate of excretion must be well characterized in the process of product development. In this work, the biodistribution of recently developed self-assembled dextrin nanoparticles is addressed. Functionalization of the dextrin nanoparticles with a DOTA-monoamide-type metal chelator, via click chemistry, is described. The metal chelator functionalized nanoparticles were labelled with a gamma-emitting (153)Sm(3+) radioisotope and the blood clearance rate and organ biodistribution of the nanoparticles were obtained. The effect of PEG surface coating on the blood clearance rate and organ biodistribution of the nanoparticles was also studied.

Design of iodine-lithium-alpha-dextrin liquid crystal with potent antimicrobial and anti-inflammatory properties.

An ideal antimicrobial should be not toxic and possess board spectrum antiviral, antibacterial, antifungal activity, excluding resistance and should affect pathogen-mediated damage of host physiology including immune, nervous and endocrine systems. With the purpose of a combination of nonspecific antimicrobial action of molecular and ionized iodine with systemic immune-modulating property of the negatively charged polysaccharides a complex drug of iodine and lithium on a template of a alpha-dextrin liquid crystal was designed. The physicochemical model of iodine-lithium-alpha-dextrin (ILalphaD) is based on the human blood and the stereochemistry of moving equilibred systems of dynamically balanced organic polymers conformation complexed with the iodine and lithium molecules. Here we reviewed the antibacterial, antiviral, immune-modulating and anti-inflammatory mechanisms in vivo and in vitro as well as pharmacokinetics, metabolism, chronic toxicity, cumulative properties, embryo toxicity and carcinogenicity of ILalphaD. Clinical efficacy, tolerability and safety of ILalphaD monotherapy have been evaluated in HIV-infected patients, administered intravenously for a total of 12 infusions in 4 cycles. ILalphaD therapy contributes to anti-HIV and anti-inflammatory effects, resolution of dermatological and neurological pathology and dramatically improves the quality of life reflecting on enhanced treatment adherence. ILalphaD appears to be safe and perspective for an adjuvant therapy of bacterial and viral infections, including HIV/AIDS, hypothyroid, autoimmune and inflammatory diseases for controlling pathogen production from infected cells, immune response, inflammation and metabolism.

A novel anti-HIV dextrin-zidovudine conjugate improving the pharmacokinetics of zidovudine in rats.

The aim of this study was to investigate a newly synthesized dextrin-zidovudine (AZT) conjugate designed as a sustained release prodrug of AZT for parenteral administration. AZT was first reacted with succinic anhydride to form a succinoylated AZT which was subsequently coupled with dextrin to yield the dextrin-AZT conjugate. The structure of the conjugate was characterized by FT-IR and (1)H-NMR spectroscopy. The drug content of the conjugate was 18.9 wt.%. The release in vitro of free AZT and succinoylated AZT was investigated in buffer solutions at pH 5.5 and 7.4 and in human plasma. AZT and succinoylated AZT release from the conjugate was 1.4% (pH 5.5), 41.7% (pH 7.4) and 78.4% in human plasma after 24 h. Release was complete in human plasma after 48 h. A pharmacokinetic study in rats following intravenous administration of the conjugate showed prolonged plasma levels of AZT compared to free AZT. The use of the conjugate extended the plasma half-life of AZT from 1.3 to 19.3 h and the mean residence time from 0.4 to 23.6 h. Furthermore, the conjugate provided a significant greater area under the plasma concentration-time curve and reduced the systemic clearance of AZT. This study suggested the potential of this novel dextrin-AZT conjugate as a new intravenous preparation of AZT.

The use of fluorescence microscopy to define polymer localisation to the late endocytic compartments in cells that are targets for drug delivery.

Macromolecular therapeutics and nano-sized drug delivery systems often require localisation to specific intracellular compartments. In particular, efficient endosomal escape, retrograde trafficking, or late endocytic/lysosomal activation are often prerequisites for pharmacological activity. The aim of this study was to define a fluorescence microscopy technique able to confirm the localisation of water-soluble polymeric carriers to late endocytic intracellular compartments. Three polymeric carriers of different molecular weight and character were studied: dextrin (Mw~50,000 g/mol), a N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer (Mw approximately 35,000 g/mol) and polyethylene glycol (PEG) (Mw 5000 g/mol). They were labelled with Oregon Green (OG) (0.3-3 wt.%; <3% free OG in respect of total). A panel of relevant target cells were used: THP-1, ARPE-19, and MCF-7 cells, and primary bovine chondrocytes (currently being used to evaluate novel polymer therapeutics) as well as NRK and Vero cells as reference controls. Specific intracellular compartments were marked using either endocytosed physiological standards, Marine Blue (MB) or Texas-red (TxR)-Wheat germ agglutinin (WGA), TxR-Bovine Serum Albumin (BSA), TxR-dextran, ricin holotoxin, C6-7-nitro-2,1,3-benzoxadiazol-4-yl (NBD)-labelled ceramide and TxR-shiga toxin B chain, or post-fixation immuno-staining for early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins (LAMP-1, Lgp-120 or CD63) or the Golgi marker GM130. Co-localisation with polymer-OG conjugates confirmed transfer to discreet, late endocytic (including lysosomal) compartments in all cells types. The technique described here is a particularly powerful tool as it circumvents fixation artefacts ensuring the retention of water-soluble polymers within the vesicles they occupy.

Improved stability of Opalmon tablets under humid conditions IV: effect of polysaccharides and disintegrants on the stability and dissolution property of Opalmon tablets.

We studied the effects of dextran, dextrin, and disintegrants on the chemical stability of Opalmon tablets containing Limaprost-alfadex (Limaprost/alpha-cyclodextrin complex) and found that the addition of dextran or dextrin significantly improved the chemical stability of Opalmon tablets under high humidity, compared to lactose. We also examined how dextran stabilizes Limaprost in Opalmon tablets and studied the formulation of Opalmon tablets in order to achieve higher chemical stability, rapid dissolution and reduced stickiness. The results suggested that dextran increases stabilization after moisture adsorption by decreasing the dissociation of Limaprost-alfadex to the free drug and alpha-cyclodextrin in the dextran matrix, when compared with the lactose matrix. The stickiness of Opalmon tablets containing dextran and dextrin was negligible when dextran and dextrin amounted to less than 20% of the formulation. By selecting a proper disintegrant, we obtained Opalmon tablets with higher chemical stability and rapid dissolution properties.

Short-term digestive tolerance of different doses of NUTRIOSE FB, a food dextrin, in adult men.

OBJECTIVE: To determine the tolerance of increasing dosages of an incompletely hydrolysed and/or incompletely absorbed food dextrin coming from wheat starch, NUTRIOSE FB, at daily levels of 10 and 15 g up to 60 and 80 g, respectively. DESIGN: A randomized, double-blind, multiple dose, placebo-controlled, combined crossover and parallel trial. SETTING: The metabolic ward of TNO Nutrition and Food Research. SUBJECTS: A total of 20 healthy men (age 31.7 +/- 9.1 y; BMI 24.5 +/- 2.9 kg/m2). INTERVENTION: One group of 10 subjects consumed on top of their diet 10, 30 and 60 g of NUTRIOSE FB or maltodextrin (placebo) daily. The other group of 10 subjects consumed 15, 45 and 80 g daily. Each dose was consumed for 7 days. RESULTS: Compared with placebo, flatulence occurred more frequently over the last 6 days on 30, 60 or 80 g/day of NUTRIOSE FB (P < 0.05). During the last 24 h, that is, days 6-7, of 60 and 80 g/day of NUTRIOSE FB, the frequency of flatulence was even higher (P < 0.05). During the last 24 h on a daily dose of 60 g NUTRIOSE FB, the frequency of defecation decreased (P < 0.05). Bloating occurred more often during the last 24 h on 80 g/day of NUTRIOSE FB (P < 0.05). None of the doses of NUTRIOSE FB resulted in diarrhoea. Compared to baseline levels, breath H2 excretion, which was only measured after a week with 10 and 15 g of NUTRIOSE FB daily, increased (P < 0.05). However, no difference in area under the curve was found. CONCLUSIONS: NUTRIOSE FB is a fermentable carbohydrate and is well tolerated up to a dose of 45 g daily. Higher daily dosages (60 and 80 g) may result in flatulence, but does not result in diarrhoea. SPONSORSHIP: TNO Nutrition and Food Research was assigned by Roquette Frères to perform the study.

Computer simulations of ultrafiltration profiles for an icodextrin-based peritoneal fluid in CAPD.

BACKGROUND: The three-pore model of peritoneal transport has the ability to predict ultrafiltration (UF) profiles rather accurately, even when high molecular weight (MW) solutes are employed as osmotic agents in continuous ambulatory peritoneal dialysis (CAPD). In the present simulations, we wanted to assess, for various theoretical perturbations, the UF properties of a peritoneal dialysis (PD) solution with an osmotic agent having an average MW of 20 kD and a "number average MW" of 6.2 kD, which is similar to that of icodextrin (ICO). METHODS: For a PD solution containing a completely monodispersed 20 kD MW osmotic agent, the degree of UF modeled is much higher than that reported for ICO. Hence, to model the behavior of ICO, we subdivided the ICO molecules into eight or more different MW size fractions. For simulations using six or eight subfractions, we obtained an excellent fit of simulated to reported UF data. More dispersed solutions produced UF profiles similar to that with eight fractions. RESULTS: A 2.05 L 7.5% ICO PD solution, despite being slightly hypotonic, yielded a UF volume of nearly 600 mL in 12 hours, modeled for patients not previously exposed for ICO. After nine hours, the UF volume exceeded that produced by 3.86% glucose. The UF rate and volumes increased in proportion to (1) the ICO concentration, (2) the peritoneal surface area, and (3) the peritoneal UF coefficient, but was almost insensitive to increases in the instilled fluid volume. Simulated for patients previously exposed to ICO, having steady-state plasma concentrations of ICO degradation products, the predicted UF volume at 12 hours was reduced to approximately 400 mL. CONCLUSION: Employing the three-pore model of peritoneal transport and taking into account the polydispersed nature of ICO, it was possible to accurately computer simulate the UF profiles of ICO in accordance with reported data. The simulations suggest an advantage of using ICO in patients with type I UF failure, where UF with a high-MW osmotic agent will exceed that seen in patients not showing UF failure who are on glucose-based PD solutions.

Reduction of the viral load of HIV-1 after the intraperitoneal administration of dextrin 2-sulphate in patients with AIDS.

OBJECTIVE: To determine the safety and efficacy of the sulphated polysaccharide, dextrin 2-sulphate, when delivered to the lymphatic circulation by the peritoneal route. DESIGN: An open Phase I/II dose-escalation clinical study in which six patients with AIDS were treated with seven courses of dextrin 2-sulphate each lasting 1 month. METHODS: During each course of treatment, the drug was administered daily for 28 days using an intraperitoneal catheter. Viral load was measured at frequent intervals using a plasma tissue culture infectious dose (TCID) assay, a cellular TCID assay, p24 antigenaemia, HIV-1 RNA and HIV-1 DNA. Plasma beta-chemokine levels were also measured. RESULTS: Dose escalation was completed without toxicity. A total of 7 patient-months of treatment were completed. With increasing doses of dextrin 2-sulphate, the infectious plasma viraemia, cellular viraemia and p24 antigenaemia all fell during the period of drug administration, but with no significant change in HIV-1 RNA. This was associated with increased plasma levels of macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. Dextrin 2-sulphate accumulated in peritoneal macrophages and induced the release of MIP-1alpha and MIP-1beta from these cells in vitro. These beta-chemokines could have augmented the cell surface-mediated anti-HIV-1 effect of dextrin 2-sulphate in vivo by binding to and blocking the CC-chemokine receptor-5. A second fall in infectious plasma viraemia, cellular viraemia, p24 antigenaemia and HIV-1 RNA was seen at day 100 which was then sustained for several months. A clinical improvement in Kaposi's sarcoma was also seen. CONCLUSIONS: Our results suggest that the intraperitoneal administration of dextrin 2-sulphate can reduce the replication of HIV-1 in patients with AIDS. With increasing doses of dextrin 2-sulphate, the fall in viral load was seen during the period of drug administration and again 2 months after completing treatment.

Optimal use of glucose polymer (icodextrin) in peritoneal dialysis.

The osmotic effectiveness of glucose polymer is now well established. The relative inertness of this macromolecular compound has been the key factor in its success as the first "colloid" osmotic agent in clinical use. In its present form, it produces sustained ultrafiltration for up to 12 hours, and a daily overnight use would obviate the need for hypertonic exchanges, especially 3.86% glucose. In addition, it could be used in automated peritoneal dialysis regimes to enhance ultrafiltration and solute clearance during the daytime. Preliminary reports also indicate that it is beneficial in diabetic patients and in some patients who have lost ultrafiltration. The new "bimodal" formulations look promising, with the potential to replace all the currently used hyperosmolar exchanges with physiological solutions. Although systemic accumulation of glucose polymer breakdown products occurs, it reaches steady-state levels quickly (within two weeks) and remains stable throughout the duration of polymer use. In the long-term study, these levels of maltose and oligosaccharides over three-and-a-half years represent the longest exposure of these substances in uremic patients without any clinical or metabolic adverse effects and provide an important evidence of safety. Future work based on studies that are ongoing suggest that a family of physiological solutions ("bimodal" preparations in iso-osmolar combination) could be available, and the individual's dialysis prescription could be tailored to take into account the ultrafiltration, metabolic needs, as well as the long-term viability of the membrane. Glucose polymer will be a key component of such solutions.

Pharmacokinetics of dipyridamole-beta-cyclodextrin complex in dogs.

Plasma concentrations and urinary and fecal excretion of intact dipyridamole were followed in dogs after oral administration of dipyridamole-beta-cyclodextrin complex (dip-beta-CD) (capsules containing 37.5 and 75 mg of active principle), of commercial dipyridamole and of dipyridamole. HCl (tablets and capsules of 75 mg of active principle, respectively), according to a crossover design. Dip-beta-CD afforded significantly shorter lag-times, higher Cmax, smaller interindividual variations of plasma concentrations and greater urinary excretion than the other two preparations, as a consequence of a better bioavailability of the former one. This amelioration seems to be due not only to an increased wettability and water solubility of the product, but also to a finer molecular dispersion in the gastrointestinal fluids which favors the contact of dipyridamole with a greater absorption surface.

[Studies on the absorption of carbohydrate and nitrogen sources in elemental diets].

To elucidate more efficient carbohydrate and nitrogen sources in elemental diets (ED), we constructed practical elemental diets in which glucose, maltose, or dextrin were used as carbohydrate sources, and crystalline amino acids (AA), small peptides (SP) or large peptides (LP) were used as nitrogen sources. We studied the absorption of carbohydrate, nitrogen and water in these elemental diets. Dogs were used as two experimental models. The Thirty-Vella loop was used as one model (a 40cm intestinal loop separated from the upper portion of the jejunum) so that the effect of digestive juice could be avoided. In the other model (jejunum fistula) two plastic tubes were indwelled in the upper portion of the jejunum, with the oral one being used for infusion of the ED and the other anal one being indwelled 40cm distal to the oral one and used for sampling of intestinal contents. In both loop models, glucose and maltose were absorbed more rapidly than dextrin. Water and nitrogen were absorbed more rapidly in the maltose-ED than glucose-ED. In another series of the studies where nitrogen sources were compared, SP was most rapidly absorbed in the AA-ED, SP-ED and LP-ED. The water absorption rate of the SP-ED was more than that of the AA-ED. These results suggest that maltose is most suitable for use as a carbohydrate source, and small peptides are most suited as a nitrogen source of the materials examined in the present study.

Determination of hydroxypropyl-beta-cyclodextrin in plasma and urine by size-exclusion chromatography with post-column complexation.

The analytical method described here provides the appropriate sensitivity and selectivity for the determination of unlabelled hydroxypropyl-beta-cyclodextrin as a parenteral carrier in pharmaceutical formulations. The method may also be used in clinical trials evaluating the fate and pharmacokinetic profile of this compound, which was isolated from the biological matrix by solid-phase extraction with Bond Elut C18 cartridges. The lack of uniformity of the product was circumvented by the use of a size-exclusion chromatographic column. An indirect colorimetric complexation method was used for detection. The detection limit was 0.1 micrograms per 2 ml of biological fluid and the extraction recovery was sufficient (78%).

Expression of ACTH-induced corticosteroid biosynthesis in newborn rat adrenocortical cells cultured in serum-free and carrier protein-free medium containing a cholesterol-alpha-cyclodextrin complex.

Newborn rat adrenocortical cells were successfully cultured in a serum-free carrier protein-free medium (SPFM) by using alpha-cyclodextrin as a cholesterol carrier and have expressed corticosteroid biosynthesis in this medium. A stable inclusion complex of cholesterol-alpha-cyclodextrin with a molar ratio of almost 1 was obtained for a 5 X 10(-5) mol/1 alpha-cyclodextrin concentration. Cell cultures incubated with [4-14C] cholesterol-alpha-cyclodextrin in SPFM produced, under ACTH stimulation, various 14C labeled steroids with a predominance of corticosterone and 18-hydroxy-11-deoxycorticosterone. As measured by gas chromatography and mass spectrometry, the ratio between corticosteroids (21-hydroxylated steroids) and 20 alpha-reduced steroids produced in SPFM with cholesterol-alpha-cyclodextrin was equal to 1.8. This corresponds to a value of 3.6 times higher than that found in the serum-free medium with cholesterol-albumin. Consequently, the chemically defined SPFM with cholesterol-alpha-cyclodextrin used in this study is more suitable for corticosteroidogenesis by adrenal cells in culture than a serum-free medium with cholesterol-albumin.