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David M Haddleton - One of the best experts on this subject based on the ideXlab platform.

Dai Nakae - One of the best experts on this subject based on the ideXlab platform.

  • Carcinogenic risk of Copper Gluconate evaluated by a rat medium-term liver carcinogenicity bioassay protocol
    Archives of Toxicology, 2008
    Co-Authors: Koji Usuda, Seigo Hayashi, Izumi Ogawa, Satoshi Furukawa, Maki Igarashi, Dai Nakae
    Abstract:

    Carcinogenic risk and molecular mechanisms underlying the liver tumor-promoting activity of Copper Gluconate, an additive of functional foods, were investigated using a rat medium-term liver carcinogenicity bioassay protocol (Ito test) and a 2-week short-term administration experiment. In the medium-term liver bioassay, Fischer 344 male rats were given a single i.p. injection of N -nitrosodiethylamine at a dose of 200 mg/kg b.w. as a carcinogenic initiator. Starting 2 weeks thereafter, rats received 0, 10, 300 or 6,000 ppm of Copper Gluconate in diet for 6 weeks. All rats underwent 2/3 partial hepatectomy at the end of week 3, and all surviving rats were killed at the end of week 8. In the short-term experiment, rats were given 0, 10, 300 or 6,000 ppm of Copper Gluconate for 2 weeks. Numbers of glutathione S -transferase placental form (GST-P) positive lesions, single GST-P-positive hepatocytes and 8-oxoguanine-positive hepatocytes, and levels of cell proliferation and apoptosis in the liver were significantly increased by 6,000 ppm of Copper Gluconate in the medium-term liver bioassay. Furthermore, hepatic mRNA expression of genes relating to the metal metabolism, inflammation and apoptosis were elevated by 6,000 ppm of Copper Gluconate both in the medium-term liver bioassay and the short-term experiments. These results indicate that Copper Gluconate possesses carcinogenic risk toward the liver at the high dose level, and that oxidative stress and inflammatory and pro-apoptotic signaling statuses may participate in its underlying mechanisms.

  • possible carcinogenic risks of Copper Gluconate and their prevention by co administered green tea catechins evaluated by a rat medium term multi organ carcinogenicity bioassay protocol
    Food and Chemical Toxicology, 2008
    Co-Authors: Noriko Suzuki, Koji Usuda, Satoshi Furukawa, Midori Yoshida, Lekh Raj Juneja, Tsutomu Okubo, Dai Nakae
    Abstract:

    Abstract Carcinogenic risks of Copper Gluconate, green tea catechins and their combined exposure were evaluated using a rat medium-term multi-organ carcinogenicity bioassay protocol. Male BrlHan:WIST@Jcl (GALAS) rats were given N -nitrosodiethylamine (DEN), N -methylnitrosourea (MNU), 1,2-dimethylhydrazine (DMH), N -butyl- N -(4-hydroxybutyl)nitrosamine (BBN) and 2,2′-dihydroxy-di- n -propylnitrosamine (DHPN) for a total multiple initiation period of 4 weeks (DMBDD treatment). Rats were then given a diet containing Copper Gluconate at a concentration of 0, 10, 300, 3000 or 6000 ppm with or without a co-administration of catechins starting 1 week later by admixing in the drinking water at a concentration of 5000 ppm. All survivors were sacrificed at the end of week 29. Number of putatively preneoplastic, glutathione S -transferase placental form-positive, liver lesions significantly increased by Copper Gluconate of 300 ppm or greater. In addition, both incidence and grade of hyperplasia in the forestomach significantly increased by Copper Gluconate of 6000 ppm. Catechins, exerting no effects by themselves, inhibited these effects of Copper Gluconate. The present results indicate that Copper Gluconate may possess carcinogenic risks for the liver and forestomach at its high dose level, and that co-administered green tea catechins may exert preventive effects.

  • preliminary evaluation of toxicologic and carcinogenic risks of Copper Gluconate in rats given multiple carcinogens
    Journal of Toxicologic Pathology, 2006
    Co-Authors: Noriko Suzuki, Koji Usuda, Satoshi Furukawa, Maki Igarashi, Midori Yoshida, Akihiko Maekawa, Lekh Raj Juneja, Tsutomu Okubo, Dai Nakae
    Abstract:

    The present study was conducted as a preliminary evaluation of toxicologic and carcinogenic risks of Copper Gluconate and to determine its optimal dose for use in an upcoming study utilizing the medium-term multi-organ carcinogenesis protocol. Male BrlHan:WIST@Jcl (GALAS) rats were initially treated with N-nitrosodiethylamine, N-methylnitrosourea, 1,2-dimethylhydrazine, N-butyl-N-(4-hydroxybutyl)-nitrosamine and 2,2'-dihydroxy-di-n-propylnitrosamine for a total multiple initiation period of 4 weeks. In addition, rats were fed a diet containing Copper Gluconate at 0, 1000, 3000, 4800, 6000, or 12000 ppm from the commencement for 13 weeks. While no systemic toxicity was detected, hepatic granulomas were observed at Copper Gluconate doses of 6000 ppm, or greater. Hepatic Copper accumulation and metallothionein induction were demonstrated at doses of 3000 ppm and 1000 ppm, respectively, or greater. Putative preneoplastic lesions in the liver appeared to increase at a dose of 12000 ppm, and 8-hydroxydeoxyguanosine formation was enhanced at doses of 6000 ppm, or greater. These results suggest that Copper Gluconate exerts effects on the liver at the relatively low dietary dose of 1000 ppm and causes hepatic injury at 6000 ppm. The hepatotoxicity and possible hepatocarcinogenicity of Copper Gluconate may be attributable to oxidative stress due to the impairment of hepatic Copper metabolism.

Athina Anastasaki - One of the best experts on this subject based on the ideXlab platform.

Lawrence D Mayer - One of the best experts on this subject based on the ideXlab platform.

  • Intra and Inter-Molecular Interactions Dictate the Aggregation State of Irinotecan Co-Encapsulated with Floxuridine Inside Liposomes
    Pharmaceutical Research, 2008
    Co-Authors: Awa Dicko, April A. Frazier, Barry D. Liboiron, Anne Hinderliter, Jeff F. Ellena, Tom Weber, Paul G. Tardi, Donna Cabral-lilly, David S. Cafiso, Lawrence D Mayer
    Abstract:

    Purpose The inter/intramolecular interactions between drugs (floxuridine, irinotecan) and excipients (Copper Gluconate, triethanolamine) in the dual-drug liposomal formulation CPX-1 were elucidated in order to identify the physicochemical properties that allow coordinated release of irinotecan and floxuridine and maintenance of the two agents at a fixed, synergistic 1:1 molar ratio. Methods Release of irinotecan and floxuridine from the liposomes was assessed using an in vitro -release assay. Fluorescence, Nuclear Magnetic Resonance spectroscopy (NMR) and UV–Vis were used to characterize the aggregation state of the drugs within the liposomes. Results Coordinated release of the drugs from liposomes was disrupted by removing Copper Gluconate. Approximately 45% of the total irinotecan was detectable in the Copper-containing CPX-1 formulation by NMR, which decreased to 19% without Copper present in the liposomal interior. Formation of higher order, NMR-silent aggregates was associated with slower and uncoordinated irinotecan release relative to floxuridine and loss of the synergistic drug/drug ratio. Solution spectroscopy and calorimetry revealed that while all formulation components were required to achieve the highest solubility of irinotecan, direct drug-excipient binding interactions were absent. Conclusions Long-range interactions between irinotecan, floxuridine and excipients modulate the aggregation state of irinotecan, allowing for simultaneous release of both drugs from the liposomes.

  • role of Copper Gluconate triethanolamine in irinotecan encapsulation inside the liposomes
    International Journal of Pharmaceutics, 2007
    Co-Authors: Awa Dicko, Paul Tardi, Lawrence D Mayer
    Abstract:

    A novel method for encapsulating irinotecan into liposomes containing Copper Gluconate buffered to pH 7.0 with triethanolamine (TEA) has recently been developed. In the present study, the mechanism dictating drug encapsulation and retention inside those liposomes was investigated. Spectroscopic analyses revealed that irinotecan interacted with Copper Gluconate/TEA in solution. Fourier transformed infrared (FT-IR) spectroscopy indicated a strengthening of the hydrogen bonds involving the hydroxyl groups when solutions of irinotecan and Copper Gluconate/TEA are mixed at a 1:1 molar ratio. The intensity of the circular dichroism (CD) signal of Copper Gluconate/TEA increased in the presence of equimolar amounts of irinotecan. The addition of irinotecan to liposomes containing Copper Gluconate/TEA at 50 °C induced a shift of the absorption bands from 370 nm to 378 nm as well as a 60% quenching of the drug fluorescence at 440 nm suggesting the occurrence of irinotecan self association. Irinotecan encapsulation was found to be kinetically and stoichiometrically correlated with the release of TEA from the liposomes. The results suggested that the encapsulation of irinotecan was mediated by TEA in association with Copper Gluconate, leading to a final drug complex that is retained inside the liposomes. A neutral antiport exchange loading mechanism between irinotecan and TEA is proposed.

  • Role of Copper Gluconate/triethanolamine in irinotecan encapsulation inside the liposomes.
    International Journal of Pharmaceutics, 2007
    Co-Authors: Awa Dicko, Paul Tardi, Lawrence D Mayer
    Abstract:

    A novel method for encapsulating irinotecan into liposomes containing Copper Gluconate buffered to pH 7.0 with triethanolamine (TEA) has recently been developed. In the present study, the mechanism dictating drug encapsulation and retention inside those liposomes was investigated. Spectroscopic analyses revealed that irinotecan interacted with Copper Gluconate/TEA in solution. Fourier transformed infrared (FT-IR) spectroscopy indicated a strengthening of the hydrogen bonds involving the hydroxyl groups when solutions of irinotecan and Copper Gluconate/TEA are mixed at a 1:1 molar ratio. The intensity of the circular dichroism (CD) signal of Copper Gluconate/TEA increased in the presence of equimolar amounts of irinotecan. The addition of irinotecan to liposomes containing Copper Gluconate/TEA at 50 °C induced a shift of the absorption bands from 370 nm to 378 nm as well as a 60% quenching of the drug fluorescence at 440 nm suggesting the occurrence of irinotecan self association. Irinotecan encapsulation was found to be kinetically and stoichiometrically correlated with the release of TEA from the liposomes. The results suggested that the encapsulation of irinotecan was mediated by TEA in association with Copper Gluconate, leading to a final drug complex that is retained inside the liposomes. A neutral antiport exchange loading mechanism between irinotecan and TEA is proposed.

  • Coencapsulation of irinotecan and floxuridine into low cholesterol-containing liposomes that coordinate drug release in vivo.
    Biochimica et Biophysica Acta, 2006
    Co-Authors: Paul Tardi, Ryan C. Gallagher, Sharon Johnstone, Natashia Harasym, Murray S. Webb, Marcel B. Bally, Lawrence D Mayer
    Abstract:

    A liposomal delivery system that coordinates the release of irinotecan and floxuridine in vivo has been developed. The encapsulation of floxuridine was achieved through passive entrapment while irinotecan was actively loaded using a novel Copper Gluconate/triethanolamine based procedure. Coordinating the release rates of both drugs was achieved by altering the cholesterol content of distearoylphosphatidylcholine (DSPC)/distearoylphosphatidylglycerol (DSPG) based formulations. The liposomal retention of floxuridine in plasma after intravenous injection was dramatically improved by decreasing the cholesterol content of the formulation below 20 mol%. In the case of irinotecan, the opposite trend was observed where increasing cholesterol content enhanced drug retention. Liposomes composed of DSPC/DSPG/Chol (7:2:1, mole ratio) containing co-encapsulated irinotecan and floxuridine at a 1:1 molar ratio exhibited matched leakage rates for the two agents so that the 1:1 ratio was maintained after intravenous administration to mice. The encapsulation of irinotecan was optimal when Copper Gluconate/triethanolamine (pH 7.4) was used as the intraliposomal buffer. The efficiency of irinotecan loading was approximately 80% with a starting drug to lipid molar ratio of 0.1/1. Leakage of floxuridine from the liposomes during irinotecan loading at 50 °C complicated the ability to readily achieve the target 1:1 irinotecan/floxuridine ratio inside the formulation. As a result, a procedure for the simultaneous encapsulation of irinotecan and floxuridine was developed. This co-encapsulation method has the advantage over sequential loading in that extrusion can be performed in the absence of chemotherapeutic agents and the drug/drug ratios in the final formulation can be more precisely controlled.

Vasiliki Nikolaou - One of the best experts on this subject based on the ideXlab platform.