NXY-059 was well tolerated at all plasma concentrations tested in both the young and elderly subjects, and no safety concerns were raised. Linear pharmacokinetics were observed following 8-h and 72-h infusions of NXY-059 at doses resulting in an average Cu(ss) in the 52-317 micromol/L range.

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The uptake of [14C]benzoic acid, 4-chloro[14C]benzoic acid, [3H]phthalic acid and [14C]salicylic acid in the nasal passages and brain was determined following a unilateral intranasal instillation in mice. An uptake of radioactivity from the nasal mucosa to the ipsilateral olfactory bulb was observed up to 4 h after administration following intranasal instillation of these carboxylic acids whereas the level was low in the contralateral olfactory bulb. Autoradiography of mice given [14C]benzoic acid and [14C]salicylic acid by intranasal instillation showed a preferential localization of radioactivity in the axonal and glomerular layer of the olfactory bulb 1 h after the administration. Four hours after administration the radioactivity was present as a gradient from the axonal layer towards the center of the olfactory bulb. Pretreatment of mice with a compound known to damage the olfactory neuroepithelium resulted in a decreased uptake of [14C]benzoic acid in the olfactory bulb. Thin layer chromatography of supernatants from the ipsilateral olfactory bulbs of mice given [14C]benzoic acid by nasal instillation indicated that the radioactivity in the bulbs represented unchanged compound. These results suggest that there is a transfer of some aromatic carboxylic acids in the olfactory pathways.

Picolinic acid (PA) protects against quinolinic acid- and kainic acid-induced neurotoxicity in the brain. To study the uptake of PA to the brain, we administered [3H]PA via a unilateral nasal instillation or iv injection to mice. Autoradiography demonstrated a rapid uptake of radioactivity in the olfactory nerve layer and in the ipsilateral olfactory bulb (OB) following nasal instillation of [3H]PA. After 4 h, there was a high level of radioactivity in the central parts of the ipsilateral OB and olfactory peduncle. Moreover, iv injection of [3H]PA demonstrated a selective uptake and retention of radioactivity in the OB. Gas chromatography-mass spectrometry (GC-MS) demonstrated the presence of PA and PA-glycine conjugate in the OB. In mice with reduced peripheral olfactory innervations there was a decreased uptake of [3H]PA in the OB as compared to controls suggesting that an intact olfactory neuroepithelium is a prerequisite for an uptake of PA to the OB. There is an increased interest in brain targeting of drugs with limited ability to pass the blood-brain barrier. The present results demonstrate that PA fulfils structural requirements for a transfer along the olfactory pathways to the brain.

Autoradiography of mice injected i.v. with bromobenzene-14C (BB; 25 mumol/kg body wt) revealed a high concentration of non-volatile metabolites in the olfactory mucosa and in the glands around the maxillary sinuses. As determined with solvent-extracted tissue sections, there was a high level of irreversibly bound metabolites in the Bowman's glands in the olfactory mucosa, while the level of bound metabolites was low in the glands around the maxillary sinuses. Histopathological examination of the nose region of mice given a single i.p. dose of unlabelled BB (greater than or equal to 4.8 mmol/kg body wt) revealed degeneration and necrosis of the glands of Bowman. Degenerative changes in the olfactory epithelium were also observed. Moreover, focal degeneration and necrosis were found in the lateral nasal glands (greater than or equal to 4.8 mmol/kg body wt). Cyst-like dilatation of acini was observed in the lateral nasal glands and in the maxillary glands located around the maxillary sinus. Incubation of BB (26 microM) with a homogenate prepared from the olfactory mucosa revealed an irreversible binding, which clearly exceeded that of the liver. It is suggested that BB is activated in situ to a cytotoxic metabolite that reacts with the glands of Bowman. The specific toxicity observed in the lateral nasal glands correlated with a high concentration of non-volatile but extractable metabolites in these glands.

This open-label, nonrandomized study assessed single and repeat ascending doses of a new sublingual fentanyl (SLF) formulation in 48 healthy Japanese opiate-naïve subjects (47 completed). Subjects received single-dose SLF 100, 200, 400, or 800 µg followed by 13 doses 6 hourly, at their dose level. Subjects taking repeat-dose 400 and 800 µg were pretreated with naltrexone in order to block opiate-receptor-mediated effects on respiration, monitored by pulse oximetry and transcutaneous pco(2). Sublingual fentanyl was rapidly and consistently absorbed. After single doses, median t(first) was 0.08 to 0.25 hours and t(max) 0.50 to 1.00 hours. After repeat dosing, median t(max) (t(max,ss)) was 0.50 to 2.00 hours. Plasma concentrations were dose proportional both after single and repeat dosing, and naltrexone appeared to have no effect on SLF pharmacokinetics. Plasma fentanyl reached steady state within the 72-hour dosing period and accumulation was approximately 2-fold. After single doses, effects on respiratory variables were evident after the 400-µg and 800-µg doses. Transcutaneous pco(2) was not helpful in detecting respiratory depression. Thus, SLF yielded rapid absorption of fentanyl and dose-proportional plasma concentrations that, for 400 µg and 800 µg, were within the typical analgesic range. Respiratory depression in these opioid-naïve volunteers was manageable with simple clinical measures.

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