Antinociceptive effect of a novel long-acting nalbuphine preparation.

BACKGROUND: A long-acting analgesic may be particularly desirable in patients suffering from long-lasting pain. The aim of the study was to evaluate the antinociceptive effect of a novel nalbuphine preparation and to determine its duration of action. METHODS: The antinociceptive effects of i.m. nalbuphine HCl in saline and nalbuphine base in sesame oil were evaluated in rats. The in vitro drug-releasing profiles of nalbuphine HCl and base in different preparations were also evaluated. RESULTS: We found that i.m. nalbuphine HCl 25, 50 and 100 micromol kg(-1) produced dose-related antinociceptive effects with a duration of action of 1.5, 2 and 3 h, respectively. i.m. nalbuphine base 100, 200 and 400 micromol kg(-1) also produced dose-related antinociceptive effects but with longer durations of action: 27, 49 and 55 h, respectively. In vitro studies demonstrated that nalbuphine base in sesame oil had the slowest drug-releasing profile of the different preparations. CONCLUSIONS: i.m. injection of an oil formulation of nalbuphine base produced a long-lasting antinociceptive effect.

A pharmacokinetic study with the high-dose anticancer agent menadione in rabbits.

The aim of this investigation was to assess the pharmacokinetic properties of high-dose menadione (VK3), as an anticancer agent, in plasma and red blood cells (RBCs) in rabbits. An extremely high dose of 75 mg menadiol sodium diphosphate (Synkayvite) was intravenously injected. HPLC analysis was applied to measure the major metabolite, menadione, VK3. The kinetic properties of VK3 in both plasma and red blood cells showed a short elimination half-life, high clearance, and large volume of distribution in plasma and RBCs. The mean elimination t1/2 values of menadione in plasma and in RBCs were 27.17 +/- 10.49 min and 35.22 +/- 11.82 min, respectively. The plasma clearance (CL/F) of VK3 was 0.822 +/- 0.254 L min-1. The systemic clearance in RBCs was 0.407 +/- 0.152 L min-1. The apparent volume of distribution (Vd/F) in plasma was 30.833 +/- 12.835 L and that in RBCs 20.488 +/- 9.401 L. The plasma AUC was 32.453 +/- 9.785 micrograms min mL-1 and that of RBCs 67.219 +/- 24.449 micrograms min mL-1. Menadiol was rapidly biotransformed to menadione in blood. The formation rate constant (kf) of menadione in plasma was 0.589 +/- 0.246 min-1, and that of RBCs 1.520 +/- 1.345 min-1. Through this study the estimated menadione dosage needed to maintain a plasma level of 1 microgram mL-1 for anticancer purposes was 19.7 mg kg-1 every hour.

Determination of anticancer drug vitamin K3 in plasma by high-performance liquid chromatography.

Synthetic vitamin K3 (VK3, 2-methyl-1,4-naphthoquinone, or menadione) has been found to exhibit antitumor activity against various human cancer cells at relative high dose. Parallel to our study on the mechanism of VK3 action and for future clinical trials in Taiwan, we developed a simple, sensitive and accurate high-performance liquid chromatographic method for the determination of VK3 in biological fluids. VK3 was extracted from the plasma samples with n-hexane. The chromatographic separation employed an ODS analytical column (5 microns, 250 x 4.6 mm I.D.) with a mobile phase of methanol-water (70:30, v/v) and UV detection at 265 nm. On completely drying of the extraction solution, n-hexane, by a stream of nitrogen, menadione was lost to a great extent. Methanol (70%, 200 microliters) was added to the extraction solvent after extraction and centrifugation to prevent the loss of menadione. The absolute recovery was 82.4 +/- 7.69% (n = 7). The within-day and between-day calibration curves of VK3 in plasma in the ranges of interest (0.01-10.00 micrograms/ml; 0.01-5.00 micrograms/ml) showed good linearity (r > 0.999) and acceptable precision. The limit of quantitation of VK3 was 10 ng/ml in plasma. This method has been successfully applied to a pilot pharmacokinetic study of VK3 in rabbits receiving an intravenous high-dose bolus injection of 75 mg menadiol sodium diphosphate (Synkayvite). The pharmacokinetic properties of menadione could be described adequately by an open two-compartment model. The mean half-life of menadiol (transformation to menadione) was 2.60 +/- 0.12 min.(ABSTRACT TRUNCATED AT 250 WORDS)

An innovative cold tail-flick test: the cold ethanol tail-flick test.

An innovative antinociceptive test, the cold ethanol tail-flick test (CET), was developed for evaluating the actions of opioid analgesics. To select an optimal operation temperature range for the CET, temperatures from -5 degrees C to -30 degrees C were screened. After screening, temperatures ranging between -20 degrees C and -30 degrees C were both strong and effective enough to act as a noxious cold stimulus. In the following study, -20 degrees C was selected as the cold stimulus for the CET. The sensitivity and specificity of this test were challenged by opioid analgesics: an agonist (morphine) and two agonist-antagonists (buprenorphine and nalbuphine), two tranquilizers (droperidol and diazepam), and four nonopioid analgesics (acetaminophen, aspirin, indomethacin, and ketoprofen). The sensitivity of the CET was also compared with the assays using heat (radiant heat and hot water). The AD50 values determined by the CET for morphine, buprenorphine, and nalbuphine were 0.16 mg/kg, 0.22 micrograms/kg, and 0.19 mg/kg, respectively. Naloxone, an opioid antagonist, blocked the antinociceptive effects of these opioids which were determined by the CET. Furthermore, the tranquilizers and nonopioid analgesics did not show any activity in the CET. Our results show that not only can the CET assess the antinociceptive activity of both opioid agonist and mixed agonist-antagonist, it also possess the characteristics of sensitivity, specificity, simplicity, and reproducibility.