The toxicity and pharmacokinetics of dihydrosanguinarine in rat: a pilot study.

The quaternary benzo[c]phenanthridine alkaloid sanguinarine (SG) is the main component of Sangrovit, a natural livestock feed additive. Dihydrosanguinarine (DHSG) has recently been identified as a SG metabolite in rat. The conversion of SG to DHSG is a likely elimination pathway of SG in mammals. This study was conducted to evaluate the toxicity of DHSG in male Wistar rats at concentrations of 100 and 500 ppm DHSG in feed for 90 days (average doses of 14 and 58 mg DHSG/kg body weight/day). No significant alterations in body or organ weights, macroscopic details of organs, histopathology of liver, ileum, kidneys, tongue, heart or gingiva, clinical chemistry or hematology markers in blood in the DHSG-treated animals were found compared to controls. No lymphocyte DNA damage by Comet assay, formation of DNA adducts in liver by 32P-postlabeling, modulation of cytochrome P450 1A1/2 or changes in oxidative stress parameters were found. Thus, repeated dosing of DHSG for 90 days at up to 500 ppm in the diet (i.e. approximately 58 mg/kg/day) showed no evidence of toxicity in contrast to results published in the literature. In parallel, DHSG pharmacokinetics was studied in rat after oral doses 9.1 or 91 mg/kg body weight. The results showed that DHSG undergoes enterohepatic cycling with maximum concentration in plasma at the first or second hour following application. DHSG is cleared from the body relatively quickly (its plasma levels drop to zero after 12 or 18 h, respectively).

One-side-coated insert as a unique ophthalmic drug delivery system.

We newly prepared a unique one-side-coated insert that releases drug from only uncoated side. The purpose of this study is to determine whether ocular and systemic absorption of ophthalmic drug could be altered by an inserting direction of the insert in rabbit eyes. One-side-coated insert was prepared by attaching a polypropylene tape on the one side of the polymer disc of poly(2-hydroxypropyl methacrylate) (HPM) containing tilisolol as a model ophthalmic drug. The insert was applied in the lower conjunctival cul-de-sac of albino rabbits with the uncoated side facing bulbar conjunctiva/sclera (SC insert) or palpebral conjunctiva (CJ insert). At the adequate intervals, the tear fluid, plasma, aqueous humor, conjunctiva, and sclera were collected and the drug concentrations were determined by an HPLC. A release of tilisolol from the one-side-coated insert was twice slower than from the uncoated insert. Ocular application of the one-side-coated insert produced the constant concentrations of tilisolol in the tear fluid over 180 min. SC insert showed higher drug concentrations in the aqueous humor and sclera, and lower drug concentrations in the plasma and conjunctiva than CJ insert.The one-side-coated insert can alter the ocular and systemic absorption of drug by an inserting direction.

Intravascular behavior of a perfluorochemical emulsion.

The purpose of this study was to clarify the reason why two similar perfluorochemical (PFC) emulsions, namely a mixed PFC (perfluorodecalin: FDC and perfluorotripropylamine: FTPA) and an FDC emulsion, resulted in a very different survival time for the exchange-transfused rats. Supposing that some difference in the intravascular behavior of both emulsions would account for such a difference in efficacy, experiments on behavior of PFC emulsions were carried out focusing on the particle size. It was reconfirmed that larger PFC particles were eliminated from the blood stream much more rapidly than smaller particles with three FMIQ (perfluoro-N-methyldecahydroisoquinoline) emulsions. After the FDC + FTPA emulsion or the FDC emulsion were injected into rabbits, PFC particles in the blood tended to decrease in size. When each of the collected blood samples was incubated at 37 degrees C for 24 h, the FDC emulsion enlarged in size markedly, but the FDC + FTPA emulsion showed no change. The retention of PFC particles appeared to depend on the emulsion stability rather than simply on the emulsifying agent alone. These data showed that some differences were observed in intravascular persistence of the FDC + FTPA emulsion and the FDC emulsion, and suggested that the efficacy of PFC emulsions would reflect their behavior in the circulation.