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The methyl ester prodrug of Nω-nitro-L-arginine (L-NAME) has been reported to exert anticancer effects against several human tumors, including thyroid carcinoma, by inhibiting nitric oxide synthase (NOS). However, chronic administration of L-NAME has often led to adverse events causing cardiovascular alterations due to its potential toxic effect. Here we report for the first time the synthesis of the galactosyl ester prodrug of Nω-nitro-L-arginine, NAGAL, a prodrug capable of inhibiting NOS more efficiently and with fewer adverse events than its parent drug. For this purpose RO82-W-1, a thyroid cell line derived from human follicular carcinoma, was used. MTT test results showed that NAGAL affected cell viability to a significantly greater extent than did L-NAME. Moreover, fluorescence activated cell sorter (FACS) analyses revealed that NAGAL, compared to L-NAME, was able to reduce nitric oxide (NO) production as well as increase the percentage of apoptotic thyreocytes. Western blot further confirmed the reduction in NOS-II expression by NAGAL. Finally, by using the LC–MS technique, we found that NAGAL elicited a higher increase in Nω-nitro-L-arginine (NA) concentration than did L-NAME. Thus, this study suggests that NAGAL could be considered a potential therapeutic tool for those pathologies involving an overproduction of NO, including thyroid carcinoma. J. Cell. Physiol. 221: 440–447, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The methyl ester prodrug of N(omega)-nitro-L-arginine (L-NAME) has been reported to exert anticancer effects against several human tumors, including thyroid carcinoma, by inhibiting nitric oxide synthase (NOS). However, chronic administration of L-NAME has often led to adverse events causing cardiovascular alterations due to its potential toxic effect. Here we report for the first time the synthesis of the galactosyl ester prodrug of N(omega)-nitro-L-arginine, NAGAL, a prodrug capable of inhibiting NOS more efficiently and with fewer adverse events than its parent drug. For this purpose RO82-W-1, a thyroid cell line derived from human follicular carcinoma, was used. MTT test results showed that NAGAL affected cell viability to a significantly greater extent than did L-NAME. Moreover, fluorescence activated cell sorter (FACS) analyses revealed that NAGAL, compared to L-NAME, was able to reduce nitric oxide (NO) production as well as increase the percentage of apoptotic thyreocytes. Western blot further confirmed the reduction in NOS-II expression by NAGAL. Finally, by using the LC-MS technique, we found that NAGAL elicited a higher increase in N(omega)-nitro-L-arginine (NA) concentration than did L-NAME. Thus, this study suggests that NAGAL could be considered a potential therapeutic tool for those pathologies involving an overproduction of NO, including thyroid carcinoma.

Synthetic zeolites were studied in order to investigate their ability to encapsulate and to release drugs. In particular, a zeolite X and a zeolitic product obtained from a cocrystallization of zeolite X and zeolite A were examined. These materials were characterized by chemical analyses (ICP-AES), X-ray diffraction, nitrogen adsorption isotherm, scanning electron microscopy, laser diffraction, and infrared spectroscopy. Since ketoprofen was chosen as a model drug for the formulation of controlled-release dosage forms, it was encapsulated into these two types of synthetic zeolites by a soaking procedure. Drug-loaded matrices were then characterized for entrapped drug amount and thermogravimetric behavior. In both types of activated zeolites, the total amount of ketoprofen (800 mg) was encapsulated in 2 g of matrix. By using HPLC measurements, ketoprofen release studies were done at different pH conditions so as to mimick gastrointestinal fluids. The absence of release in acid conditions and a double phased release, at two different pH values (5 and 6.8), suggest that after activation these materials offer good potential for a modified release delivery system of ketoprofen.

Fluorescent ligands for the peripheral-type benzodiazepine receptor (PBR) featuring the 7-nitrobenz-2-oxa-1,3-diazol-4-yl moiety were synthesized, based on N,N-dialkyl-2-phenylindol-3-ylglyoxylamides, a potent, selective class of PBR ligands previously described by us. All the new ligands are moderately to highly potent at the PBR, with a complete selectivity over the central benzodiazepine receptor. Results from fluorescence microscopy showed that these probes specifically labeled the PBR at the mitochondrial level in C6 glioma cells.