Rutaecarpine is an indolopyridoquinazolinone alkaloid isolated from Evodia rutaecarpa and related herbs, which has shown a variety of intriguing biological properties such as anti-thrombotic, anticancer, anti-inflammatory and analgesic, anti-obesity and thermoregulatory, vasorelaxing activity, as well as effects on the cardiovascular and endocrine systems. Recent progress in the studies on the isolation, synthesis, structure-activity relationship studies, biological activities and metabolism of rutaecarpine are reviewed.

In commercial products such as household deodorants or biocides, didecyldimethylammonium chloride (DDAC) often serves as an antimicrobial agent, citral serves as a fragrance agent, and the excipient ethylene glycol (EG) is used to dissolve the active ingredients. The skin sensitization (SS) potentials of each of these substances are still being debated. Moreover, mixtures of DDAC or citral with EG have not been evaluated for SS potency. The in vitro alternative assay called human Cell Line Activation Test (h-CLAT) and Direct Peptide Reactivity Assay (DPRA) served to address these issues. On three independent runs of h-CLAT, DDAC and citral were predicted to be sensitizers while EG was predicted to be a non-sensitizer and also by the DPRA. Mixtures of DDAC or citral with EG at ratios of 7:3 and 1:4 w/v were all positive by the h-CLAT in terms of SS potential but SS potency was mitigated as the proportion of EG increased. Citral and its EG mixtures were all positive but DDAC and its EG mixtures were all negative by the DPRA, indicating that the DPRA method is not suitable for chemicals with pro-hapten characteristics. Since humans can be occupationally or environmentally exposed to mixtures of excipients with active ingredients, the present study may give insights into further investigations of the SS potentials of various chemical mixtures.

Racemic sibutramine is widely used to treat obesity owing to its inhibition of serotonin and noradrenaline reuptake in synapses. Although the enantioselective effects of sibutramine and its two active desmethyl-metabolites, monodesmethylsibutramine (MDS) and didesmethylsibutramine (DDS), on anorexia and energy expenditure have been elucidated, the enantioselective pharmacokinetics of sibutramine are still unclear. Therefore, we aimed to characterize the enantioselective pharmacokinetics of sibutramine and its metabolites in plasma and urine following an intravenous and a single oral administration of sibutramine in rats. The absolute bioavailability of sibutramine was only about 7%. The pharmacologically less effective S-isomer of DDS was predominant in the plasma: the C ( max ) and the AUC ( inf ) were 28 and 30 times higher than those of the R-isomer, respectively (p<0.001). In the urine, the concentrations of the R-isomers of hydroxylated DDS and hydroxylated and carbamoylglucuronized MDS and DDS appeared to be 11.3-, 5.1-, and 5.3-times the concentrations of the respective S-isomers. Thus, regardless of increased potency than the S-enantiomers, the R-enantiomers of the sibutramine metabolites MDS and DDS were present at lower concentrations, owing to their rapid biotransformation to hydroxylated and/or carbamoylglucuronized forms and their faster excretion in the urine. The present study is the first to elucidate the enantioselective pharmacokinetics of sibutramine in rats.

Colorectal cancer is among the most common human malignancies, and remains a leading cause of cancer-related morbidity and mortality. Patients with rectal cancer, despite surgery, still have a significant probability of relapse and cancer-related death. Adjuvant treatment is a rapidly evolving field of rectal cancer treatment. The standard approach is a combination of chemotherapy and radiation therapy (RT). The combined chemotherapy and RT for rectal cancer has been shown to increase the proportion of patients cured of their disease.1,2) 5-Fluorouracil (5-FU) has been widely used in the treatment of solid malignancies.3,4) 5-FU administered via suppository has shown less systemic toxicity, while permitting direct topical contact to rectal cancer and higher rectal tissue concentrations than intravenous administration. 5,6) 5-FU is also used as an adjuvant chemotherapeutic agent for rectal cancers.1) It has also been reported that 5-FU suppository delivery combined with radiation causes less systemic toxicity and is more effective than intravenous administration. 7)A conventional rectal suppository such as a suppository formulated with a polyethylene glycol base, which may soften or melt slowly in the site of application due to its relatively high melting point, cannot be rapidly absorbed in the mucous membranes of the absorption site. 8,9) Furthermore, conventional suppositories, which may reach to the end of the canal of the application site, because of its poor mucoadhesive properties, lose drugs at that level, and may also allow the carried drugs to undergo the first-pass effect.10) To solve these problems associated with the use of conventional solid suppository, it would be desirable to develop a novel solid suppository, which was a solid phase at room temperature and instantly melted at physiological temperature, and had mucoadhesive properties to such level that it would attach to the site of application, i.e. the rectal mucous membranes. 11)Recently, we have established the mixture composed of poloxamer 188 (P188) and propylene glycol (PG) for suppository having the suitable melting point (30-37°C) and mucoadhesive property. 12)Thus, the purpose of this study is to investigate whether the solid suppository with P188 and PG is a candidate of rectal dosage form for 5-FU in treating not only rectal cancers but skin cancers in mice. MATERIALS AND METHODS MaterialsThe murine CT-26 colon carcinoma cell line was purchased from Korean Cell Line Bank (Seoul, Korea). Fetal bovine serum (FBS) was purchased from GIBCO (Grand Island, NY, U.S.A.). 5-FU was provided by Dong-A Chemical (Seoul, South Korea). P188 which is a copolymer of poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) with the ratio of POE/POP of 80/20 and the molecular weight of 8350 was obtained from BF Goodrich (Breesville, OH, U.S.A.), and PG was from DC Chemical Co., Ltd. (Seoul, South Korea). Propylene glycol was of USP grade. The semipermeable membrane tube (Spectra membrane tubing No. 1) was from Spectrum Medical Industries Inc. (Los Angele...

Glimepiride, a second-generation sulfonylurea, is a glucose-lowering agent widely used to treat diabetes mellitus. It is converted into metabolite M1 by CYP2C9, and M1 is then transformed into the carboxyl derivative M2 by cytosolic enzymes. In this study, we introduce a sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for determining glimepiride, M1, and M2 in human plasma. After simple protein precipitation with acetonitrile, the analytes were chromatographed on a reversed-phase CN column with a mobile phase of 10 mM ammonium acetate aqueous solution and acetonitrile (1:1, v/v). The accuracy and precision of the assay were in accordance with FDA regulations for the validation of bioanalytical methods. This method was used to measure the concentrations of glimepiride, M1, and M2 in plasma after a single oral 2-mg dose of glimepiride in volunteers.