Novel depots of buprenorphine prodrugs have a long-acting antinociceptive effect.

An analgesic with a prolonged duration may be desirable in patients with long-lasting pain. In this study, we evaluated the antinociceptive effects and durations of action of three novel depots of buprenorphine esters buprenorphine propionate, enanthate, and decanoate given by IM injection, in rats. The pharmacokinetic profiles of buprenorphine in blood after IM injection of these depots were also evaluated. Antinociception was evaluated using the plantar test. Buprenorphine concentrations in blood were assayed using high-performance liquid chromatography. We found that the traditional form of buprenorphine HCl (in saline) produced a dose-related antinociceptive effect. A dose of 0.6 micromol/kg buprenorphine HCl (in saline) produced a significant antinociceptive effect lasting 5 h. The same dose of buprenorphine base, propionate, enanthate, and decanoate (in oil) also produced a significant antinociceptive effect with longer durations of action of 26, 28, 52, and 70 h, respectively. The pharmacokinetic studies demonstrated that all the buprenorphine esters were prodrugs of buprenorphine. We conclude that the novel depots of buprenorphine prodrugs: buprenorphine propionate, enanthate, and decanoate produced a long-acting antinociceptive effect after IM injection in rats.

Novel depots of buprenorphine have a long-acting effect for the management of physical dependence to morphine.

Buprenorphine is a promising new pharmacotherapy for the management of physical dependence to opioids. The aim of the study was to evaluate the duration of action of several novel depots of buprenorphine in the treatment of physical dependence to morphine in mice. Following intramuscular injection, the duration of action of several novel oil-based depots of buprenorphine base in morphine-dependent mice were evaluated. The traditional dosage form of buprenorphine hydrochloride in saline was used as control. We found that the depot of buprenorphine base in sesame oil produced a dose-related long-lasting effect. On an equimolar basis of 6 micromol kg(-1), its effect was 5.7-fold longer than that of buprenorphine hydrochloride in saline. When prepared in several other oleaginous vehicles (castor oil, cottonseed oil, peanut oil and soybean oil), buprenorphine base also produced a long-lasting effect, which was similar to buprenorphine base in sesame oil. In conclusion, buprenorphine base, when prepared in oleaginous vehicles and injected intramuscularly in mice, produced a long-lasting effect on physical dependence to morphine.

Human PCDD/PCDF levels near a pentachlorophenol contamination site in Tainan, Taiwan.

A pentachlorophenol (PCP) manufacturing plant in southern Taiwan discontinued production in 1989. The site of the abandoned plant was heavily contaminated by PCDD/PCDFs, impurities formed in the PCP production process. Serum samples collected from 27 residents living near the deserted plant were evaluated to determine whether this contamination had associated serum levels of PCDD/PCDFs in local residents. The average level of 17 tested congeners ranged from 556 to 5240 pg/g lipid (mean, 1670 pg/g lipid). The corresponding 2,3,7,8-TCDD toxicity equivalent quotient values calculated by international toxicity equivalent factors (I-TEFs) and those recommended by WHO (WHO-TEFs) were 47.2 pg I-TEQ/g lipid and 53.4 pg WHO-TEQ/g lipid, respectively. Levels in other parts of Taiwan typically range from 15 to 20 pg WHO-TEQ/g lipid; therefore, it is likely that the heavily contaminated plant site caused these unusually high serum levels. The average PCDD/PCDF levels of 29 fish-tissue and nine soil samples collected from the sea reservoir surrounding the abandoned PCP plant were also abnormally high: 8630 pg/g lipid (985 pg WHO-TEQ/g lipid) and 606000 pg/g-sample (922 pg WHO-TEQ/g-sample), respectively. Factor analysis indicated that the congener pattern of human serum samples collected from residents living near the abandoned PCP plant different from samples collected from other areas in Taiwan without known PCDD/PCDF pollution. Similar results were observed for the fish tissue and soil samples. The current study may have discovered a "hot spot" for elevated dioxin human exposure in Taiwan. The preliminary finding has raised a public health concern in the inspected area and requires further investigations to clarify the nature of the contamination and potential impact on the local environment and human health.

Simultaneous determination of buprenorphine and its prodrug, buprenorphine propionate, by high-performance liquid chromatography with fluorescence detection: application to pharmacokinetic studies in rabbits.

A rapid, sensitive, precise and accurate high-performance liquid chromatographic assay with fluorescence detection was developed for the simultaneous determination of buprenorphine and buprenorphine propionate in human and animal blood. Buprenorphine propionate was also proven to be a prodrug of buprenorphine. It was comprised of only a one-step extraction procedure with ethyl acetate and normal-phase chromatography on a Betasil Silica column. The recoveries of buprenorphine and buprenorphine propionate were above 84%. Calibration graphs were linear for buprenorphine over the concentration range 2-1500 ng/ml and for buprenorphine propionate over the concentration range 20-1500 ng/ml with a coefficient of variation, both within- and between-day, or less than 10% at any level. The limits of quantitation of buprenorphine and buprenorphine propionate in human or animal blood were 2.0 and 20 ng/ml, respectively, based on a single-to-noise ratio of 3. The method has been successfully applied to pharmacokinetic studies of buprenorphine and buprenorphine propionate in rabbits. The results demonstrated that buprenorphine propionate was rapidly and totally converted to its parent drug, buprenorphine, following intravenous administration. Buprenorphine propionate is a prodrug of buprenorphine.

The depot of buprenorphine decanoate produced a dose-related long-lasting antinociceptive effect in guinea pigs.

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 depot of buprenorphine decanoate and its metabolic profiles in human and animal blood. METHODS: Following their intramuscular injections in guinea pigs, the antinociceptive effects of the novel depot of buprenorphine decanoate (in oil) and the traditional dosage form of buprenorphine HCl (in saline) were evaluated. An in vitro metabolic study of buprenorphine decanoate in human and animal blood was also carried out. The antinociception of drugs was evaluated using the plantar test. The blood concentrations of drugs were assayed using a high performance liquid chromatography. RESULTS: We found that both the buprenorphine HCl (in saline) and buprenorphine decanoate (in oil) produced dose-related antinociceptive effect but of different duration of action. Under an equi-mole basis of 0.6 micromol/kg, the durations of action of buprenorphine HCl and decanoate were 4 and 72 h, respectively. In in vitro metabolic study in human and animal bloods, buprenorphine decanoate was totally converted to buprenorphine. Buprenorphine decanoate is a prodrug of buprenorphine. CONCLUSIONS: Intramuscular injection of the depot of buprenorphine decanoate in guinea pigs produced a dose-related long-lasting antinociceptive effect which was much longer than that of the traditional dosage form of buprenorphine HCl. Moreover, buprenorphine decanoate is a prodrug of buprenorphine.