ABSTRACT:Bicifadine [DOV 220,075; (؎)-1-(4-methylphenyl)-3-azabicyclo[3.1.0]-hexane HCl)] is a non-narcotic analgesic that is effective in animal models of acute and chronic pain. In this study, the pharmacokinetics, disposition, and metabolism of bicifadine were determined in male and female mice, rats, and cynomolgus monkeys following single oral and i.v. doses. [ 14 C]Bicifadine was well absorbed in all three species. The oral bioavailability of bicifadine in mice and rats was 50 to 63% and 79 to 85%, respectively, and slightly lower in monkeys (33-42%). Based on the values of the area under the concentration-time curves, unchanged bicifadine comprised 7 to 12% of the plasma radioactivity after the oral dose and 14 to 26% after the i.v. dose in all three species. The major plasma metabolites were the lactam (M12), the lactam acid (M9), and the acid (M3) plus its glucuronide conjugate. At 0.5 h after the oral dose to rats, 63 to 64% of the radioactivity in the rat brain was bicifadine, and the remainder was the lactam. Most of the radioactivity after oral and i.v. dosing to the three species was recovered in the urine. The lactam acid was the major urinary metabolite in all species; bicifadine and the lactam were either not detected or were minor components in urine. Fecal radioactivity was due to the acid and lactam acid in the three species. Rat bile contained mainly the lactam acid and the acid plus its acyl glucuronide. Plasma protein binding of [ 14 C]bicifadine was moderate in the mouse (80-86%) and higher in the rat and monkey (95-97%). In summary, bicifadine was well absorbed, extensively metabolized, and excreted via the urine and feces as metabolites.Bicifadine (Fig. 1) is an inhibitor of norepinephrine and serotonin uptake that is being developed for the treatment of acute and chronic pain. The compound is a non-narcotic analgesic (Epstein et al., 1982) that is active in preclinical models of neuropathic pain. In animals, bicifadine has been shown to inhibit dopamine uptake, thus making it a functional triple reuptake inhibitor with antinociceptive and antiallodynic activity in acute, persistent, and chronic pain models (Basile et al., 2007). Clinically, it has been shown to be effective in the treatment of acute dental (Stern et al., 2005) and bunionectomy pain (Riff et al., 2006).The metabolites of bicifadine formed by mouse, rat, monkey, and human hepatocytes and microsomes were reported previously (Erickson et al., 2007). The two main metabolic pathways in all four species were formation of a lactam and the oxidation of the tolylmethyl group. When tested in human in vitro systems, MAO-B was the principal enzyme that formed the lactam, whereas CYP2D6 was responsible for the initial hydroxylation of the tolylmethyl group. The present studies were performed to determine the pharmacokinetics, metabolism, and disposition of bicifadine in the mouse, rat, and monkey, the species used in toxicological and carcinogenicity studies. Materials and MethodsChemicals and Reagents. [ Animal Studies. All experim...

The North Atlantic Treaty Organization (NATO), the Southeast Asia Treaty Organization (SEATO), and the Central Treaty Organization (CENTO) were consid ered necessary in the postwar period to protect member-coun tries from Communist aggression and conspiracy. Subsequent developments have not always reflected the tidiness of inflexible and implacable confrontation, however. Thus, the viability of this postwar structure of alliances is raised ever more insist ently. Do NATO, SEATO, and CENTO serve any longer the interests of the West? Or has the time now arrived for their complete reappraisal? The view gains ground in western Europe that there is now considerable diversity in the Com munist world, and that a policy of positive coexistence should be pursued in the tackling of common problems with such coun tries as are ready to do so. In this fluid situation, a policy of movement is desirable, especially in Europe, where economic as well as political initiatives on behalf of a reconstructed NATO can provide pointers for the continued viability of CENTO and SEATO. The pending renegotiation of the NATO Pact can provide such economic initiatives. It can also provide the model of a self-supporting security system under the Soviet-American nuclear balance.

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Although ‘Anthropocene’ is a relatively new term, the idea of anthropogenic environmental change has a long, rich and underappreciated history. This study traces the development of a narrative of human-caused climate change in southern France in the first half of the nineteenth century that mirrored today’s rhetoric of the Anthropocene, and it exposes the interplay of social and environmental forces in the establishment of this narrative. Drawing on natural archives and instrumental data as well as traditional archival sources and contrasting these indices with literature on Alpine flooding from the period, it maps French intellectual environmental perceptions against the realities of climate and weather in early nineteenth-century Provence. In this context, concerns about human influence on the climate stemmed less from actual climate change than from major social transformations, which made inhabitants of Provence increasingly aware of and susceptible to environmental forces, and flooding in particular. Through this case study, the paper exposes the importance of recognising and accounting for human perceptions in charting environmental change. It also contributes to environmental history by identifying late Little Ice Age conditions in Mediterranean France, and it reaffirms the value of an interdisciplinary, integrative approach to the study of climate change.

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