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Each integrable lowest weight representation of a symmetrizable Kac-Moody Lie algebra g has a crystal in the sense of Kashiwara, which describes its combinatorial properties. For a given g, there is a limit crystal, usually denoted by B(−∞), which contains all the other crystals. When g is finite dimensional, a convex polytope, called the Mirković-Vilonen polytope, can be associated to each element in B(−∞). This polytope sits in the dual space of a Cartan subalgebra of g, and its edges are parallel to the roots of g. In this paper, we generalize this construction to the case where g is a symmetric affine Kac-Moody algebra. The datum of the polytope must however be complemented by partitions attached to the edges parallel to the imaginary root δ. We prove that these decorated polytopes are characterized by conditions on their normal fans and on their 2faces. In addition, we discuss how our polytopes provide an analog of the notion of Lusztig datum for affine Kac-Moody algebras. Our main tool is an algebro-geometric model for B(−∞) constructed by Lusztig and by Kashiwara and Saito, based on representations of the completed preprojective algebra Λ of the same type as g. The underlying polytopes in our construction are described with the help of Buan, Iyama, Reiten and Scott's tilting theory for the category Λ-mod. The partitions we need come from studying the category of semistable Λ-modules of dimension-vector a multiple of δ.One of these tools is Buan, Iyama, Reiten and Scott's tilting ideals for Λ [14]. Let S i be the simple Λ-module of dimension-vector α i and let I i be its annihilator, a one-codimensional two-sided ideal of Λ. The products of these ideals I i are known to satisfy the braid relations, so to each w in the Weyl group of g, we can attach a two-sided ideal I w of Λ by the rule I w = I i 1 · · · I i ℓ , where s i 1 · · · s i ℓ is any reduced decomposition of w. Given a finite-dimensional Λ-module T , we denote the image of the evaluation map I w ⊗ Λ Hom Λ (I w , T ) → T by T w .Recall that the dominant Weyl chamber C 0 and the Tits cone C T are the convex cones in the dual of RI defined asWe will show the equality T min θ = T max θ = T w for any finite dimensional Λ-module T , any w ∈ W and any linear form θ ∈ wC 0 . This implies that dim T w is a vertex of Pol(T ) and that the normal cone to Pol(T ) at this vertex contains wC 0 . This also implies that Pol(T ) is contained inWhen θ runs over the Tits cone, it generically belongs to a chamber, and we have just seen that in this case, the face P θ is a vertex. When θ lies on a facet, P θ is an edge (possibly degenerate). More precisely, if θ lies on the facet that separates the chambers wC 0 and ws i C 0 , with say ℓ(ws i ) > ℓ(w), then (T min θ , T max θ ) = (T ws i , T w ). Results in [1] and [27] moreover assert that T w /T ws i is the direct sum of a finite number of copies of the Λ-module I w ⊗ Λ S i .There is a similar description when θ is in −C T ; here the submodules T w of T that come into play are the kernels of the coevaluation maps T → ...

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Pharmacokinetic measurements, neuroendocrine responses, and side effects profiles of intravenous infusions of 20 mg citalopram over 30 minutes during the early afternoon have been studied. Eight healthy male volunteers were enrolled in a placebo- (saline) controlled, single-blind, cross-over protocol. Plasma concentrations of the parent compound showed a double exponential decay. Demethyl and didemethyl metabolites were not detectable, but low concentrations of the propionic acid derivative of citalopram were found. Determination of the citalopram enantiomers yielded a balanced S(+)/R(-) ratio of 0.9 to 1.2. The endocrine response to the drug was characterized by significant increases in plasma prolactin and cortisol. Except for one subject, who developed pronounced side effects, human growth hormone showed a surge following saline that was inhibited following citalopram. Rectal temperature and heart rate were not affected and tolerability was favorable. Because of citalopram's extremely high selectivity for the presynaptic 5-hydroxytryptamine nerve terminals, the present data suggest that it might be a promising tool for the investigation of serotonergic function in the human brain in vivo.

Sixty-nine depressive patients (DSM III criteria: 296.2, 296.3, 296.5, 300.4) were treated with 40 to 60 mg citalopram (CIT) daily for 4 weeks. Among them, 45 responded to treatment (improvement > 50% on the 21-item Hamilton Rating Scale for Depression [HAM-D]) and continued their treatment for another week before being released from the study. The 24 nonresponders were randomized and comedicated under double-blind conditions with lithium carbonate (Li) (2 x 400 mg/day) (CIT-Li group) or with placebo (CIT-Pl group) from days 29 to 35. For days 36 to 42, the patients of both subgroups were treated openly with Li (800 mg/day) in addition to the ongoing CIT treatment. On day 35, 6 of 10 patients responded to the CIT-Li combination, whereas 2 of 14 patients only responded to the CIT-Pl combination. This group difference reached significance (p < 0.05) on day 35 with lower HAM-D total scores in the CIT-Li group. No evidence was seen of a pharmacokinetic interaction between CIT and Li, and this combination was well tolerated. Patients were phenotyped with dextromethorphan and mephenytoin at baseline and at day 28. As evaluated at baseline, three patients (responders) were poor metabolizers of dextromethorphan and six patients (three responders and three nonresponders) of mephenytoin. On day 28, the ratio CIT/N-desmethylCIT (DCIT) in plasma was significantly higher in poor than in extensive metabolizers of mephenytoin (p = 0.0001), and there was a significant positive correlation between the metabolic ratio of dextromethorphan and the ratio DCIT/N-didesmethylCIT in plasma (p < 0.001). These findings illustrate the role of CYP2D6 and CYP2C19 in the metabolism of CIT. It can be concluded that Li addition to CIT is effective in patients not responding to CIT alone without any evidence of an accentuation or provocation of adverse events.

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The recently introduced antidepressants, the selective serotonin reuptake inhibitors (SSRIs) [citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline], are known for their clinical efficacy, good tolerability and relative safety. They differ from each other in chemical structure, metabolism and pharmacokinetic properties. Therapeutic drug monitoring of these compounds is not widely used, as the plasma concentration ranges within which clinical response with minimal adverse effects appears to be optimal are not clearly defined. Almost all recent assays developed for the quantitative determination of SSRIs and their metabolites in blood are based either on the separation of SSRIs by high performance liquid chromatography (HPLC) or gas chromatography (GC). Citalopram and fluoxetine have been introduced as racemic compounds. There are some differences in the pharmacological profile, metabolism and pharmacokinetics between the enantiomers of the parent compounds and their demethylated metabolites. Stereoselective chromatographic methods for their analysis in blood are now available. With regard to the SSRIs presently available, no clearcut plasma concentration-clinical effectiveness relationship in patients with depression has been shown, nor any threshold which defines toxic concentrations. This may be explained by their low toxicity and use at dosages where serious adverse effects do not appear. SSRIs vary widely in their qualitative and quantitative interaction with cytochrome P450 (CYP) isozymes in the liver. CYP2D6 is inhibited by SSRIs, in order of decreasing potency paroxetine, norfluoxetine, fluoxetine, sertraline, citalopram and fluvoxamine. This may have clinical consequences with some but not all SSRIs, when they are taken with tricyclic antidepressants. Except for citalopram and paroxetine, little is known about the enzymes which control the biotransformation of the SSRIs. There have been many reports on marked pharmacokinetic interactions between fluoxetine and tricyclic antidepressants. Fluoxetine has a stronger effect on their hydroxylation than on their demethylation. Interactions observed between fluoxetine and alprazolam, midazolam and carbamazepine seem to occur on the level of CYP3A. Fluvoxamine strongly inhibits the N-demethylation of some tricyclic antidepressants of the tertiary amine type and of clozapine. This may lead to adverse effects but augmentation with fluvoxamine can also improve response in very rapid metabolisers, as it increases the bioavailability of the comedication. Fluvoxamine inhibits with decreasing potency, CYP1A2, CYP2C19, CYP2D6 and CYP1A1, but it is also an inhibitor of CYP3A. Fluoxetine and fluvoxamine have shown to increase methadone plasma concentrations in dependent patients. Some authors warn about a combination of monoamine oxidase (MAO) inhibitors with SSRIs, as this could lead to a serotonergic syndrome. Studies with healthy volunteers suggest, however, that a combination of moclobemide and SSRIs, such as fluvoxamine, should not present serious risks in prom...

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