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The brain/plasma partition of nefazodone, hydroxynefazodone (OHNFZ) and m-chlorophenyl-piperazine (mCPP) and their antagonism of p-chloroamphetamine (PCA)-induced 5-hydroxytryptamine (5-HT) depletion and quipazine-induced head twitches were compared in rodents. Nefazodone (30 mg kg(-1), i.p.) rapidly entered the brain but concentrations were exceeded by mCPP, the metabolic ratio being 47 and 10 in the mouse and rat respectively. OHNFZ was detectable in plasma but never in brain. Brain concentrations of OHNFZ in the mouse (30 mg kg(-1), i.p.) were less than 10% of those in plasma, confirming a poor blood-brain barrier penetration. Concentrations of its metabolite mCPP were similar to those after 5 mg kg(-1)(i.p.) mCPP. In the mouse, nefazodone (30 mg kg(-1)) antagonized the 5-HT depleting effect of PCA 2 h after dosing, when it had disappeared from brain but when mCPP concentrations were similar to those after 5 mg kg(-1) (i.p.) mCPP. However, mCPP antagonized PCA less than nefazodone. In the rat, nefazodone pretreatment (30 mg kg(-1), 15 min) prevented (97% of inhibition) quipazine-induced head twitches. The effect was weaker (65% of inhibition) but significant when only mCPP was detected in brain. Analysis of brain concentrations of the two compounds after their ED50 against quipazine indicated that both contributed to the effect, although nefazodone was more active than mCPP in terms of concentrations required to obtain a comparable reduction of twitches. These findings show that mCPP concentrates in the brain following injection of nefazodone and may play a role in preventing quipazine-induced behaviour and PCA-induced 5-HT depletion. In contrast OHNFZ poorly enters the brain and its in vivo activity is mostly due to its biotransformation to mCPP.

The pharmacokinetics and safety of CL 275,838, a new potential memory-enhancing compound, were examined after 14 daily doses (50 and 100 mg) in 16 healthy male volunteers, age 20 to 59 years, in a randomized, double-blind, placebo-controlled, parallel group study. Trough blood samples (predose) were collected on days 2, 4, 7, 10, and 14, and further samples were drawn after the final dose (day 14) to define the multiple-dose kinetics of the parent compound and its metabolites II and IV. Intercurrent clinical events, vital functions, EEG, ECG, and cognitive tests (attention, verbal memory, and spatial memory) were considered as outcome measures of safety. Performance in cognitive tests was also studied to collect preliminary information on possible therapeutic action. Predose plasma concentrations of the parent compound and its two metabolites increased approximately in proportion to the dose, and accumulation was complete within 7 days, regardless of the dose. At steady state, mean Cmax and AUC of the parent compound and its two metabolites were dose related. Mean wash-out t1/2 was 18 to 20 hours for the parent compound, 22-23 hours for metabolite II, and 28-33 hours for metabolite IV; these elimination t1/2 are comparable for the two doses, and are similar to those observed in single-dose studies. For the 50-mg-dose group, predicted and observed average plasma concentrations (Css) of CL 275,838 and its two metabolites did not differ significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics and safety of CL 275,838, a potential cognition-enhancing compound, were studied after single escalating oral doses first in young healthy male volunteers and then in old (60-74 years) and very old (over 75 years) volunteers of both sexes. In all age groups absorption of CL 275,838 was rapid as assessed by the mean time to reach maximum plasma concentrations (Cmax) which averaged 1-2 hr, regardless of the dose administered. In young male volunteers both Cmax and area under the curve (AUC) increased proportionally with dose from 10 to 100 mg. Mean elimination half-lives (t1/2) of the parent compound (18-21 hr) and of its circulating metabolites II (20-22 hr) and IV (27-30 hr) were well comparable for the doses tested (50 and 100 mg). Age did not appreciably affect plasma Cmax of CL 275,838 or its two metabolites. Mean AUC and elimination half-life did not appreciably differ between old and very old subjects given 50 mg CL 275,838, with the limitations dictated by the small number of elderly subjects examined. Compared with younger volunteers receiving comparable doses, however, the elderly had higher mean plasma AUC of the unchanged compound and its two metabolites, although the parameter varied widely between subjects. The mean elimination t1/2 (+/- SD) was longer in the elderly (38.8 +/- 19.6, 50.5 +/- 24.5 and 41.7 +/- 12.1 hr, respectively, for the parent compound and its metabolites II and IV) than in the young subjects. The cause(s) of these variations and the possible clinical implications remain to be established.(ABSTRACT TRUNCATED AT 250 WORDS)

We report a case of pancreatic tumour metastatic to the liver in a patient with insulin-treated diabetes, anaemia, cheilitis, necrolytic migratory erythema, hypokalemia and chronic watery diarrhea, a picture suggesting combined glucagonoma and VIPoma syndromes. Immunocytochemistry of a biopsied hepatic metastatic nodule revealed both glucagon and vasoactive intestinal peptide (VIP) positive cells. Increased plasma glucagon and VIP levels were detected (values of 900 pmol/l and 277 pmol/l respectively). This is the first reported case showing not only immunocytochemical, but also clinical evidence of the combined secretion of these hormones.