Asmasal

Powder for inhalation Ventodisks Accuhaler Rotacaps Asmasal Qickhaler A H A H A H Medeva 200 and 400 pg/inhalation 200 pg/inhalation 200 and 400 pg/inhalation 95 pg/inhalation... 

The lysosomal acid sphingomyelinase (aSMase) isoform is inhibited by L-camitine, a cofactor of acyl-coenzyme A transport in mitochondria (107, 108), and by phosphatidylinositol polyphosphates, which occur in plant, yeast, and mammalian cells (109). 

Inliibitors of aSMase are also known, such as the xanfhone u-rnangoslin, isolated from the bark of Garcinia speciosa [116] u-rnangoslin has recently been obtained by organic synthesis [117]. 

Figure 10.5 Device categories (clockwise from left) single-capsule, Spinhaler (Aventis), multi-dose reservoir, Pulmicort (AstraZeneca), multi-dose reservoir, Asmasal Clickhaler (Medeva), and multi-dose pre-metered, Flixotide Accuhaler (GlaxoWellcome).

Deigner, H-P, Claus, R, Bonaterra, G A, Gehrke, C, Bibak, N, Blaess, M, Cantz, M, Metz, J, and Kinscherf, R, Ceramide induces aSMase expression Implications for oxLDL-induced apoptosis, FASEB J. 15 (2001) 807-814. 

Some years ago, the involvement of ASMase in apoptosis mediated through the Fas/CD95-receptor had been discussed controversially in the literature (Bezombes et al., 2001 Cock et al., 1998 De Maria et al., 1998 Kirschnek et al., 2000). However, the work of R.Kolesnick and co-workers (Lin et al., 2000) clarified by in vivo experiments on ASMase-deficient mice that ASMase-derived ceramide mediates Fas-mediated apoptosis in some cell types (in particular hepatocytes), but not in others (e.g., thymocytes, T-lymphocytes). This explains why ASMase deficient mice are less susceptible to lethality and liver apoptosis induced by the anti-Fas antibody Jo-2, but do not develop lymphoproliferative disease like Ipr mice that lack functional CD95. We note, however, that the reason for the observed cell type specificity is not known, and that... 

CD95-induced apoptosis in the human T-cell line Jurkat ean be readily inhibited by bloeking aSMase (A.Billich, unpublished data). 

The funetional link between Fas-induced apoptosis, eeramide and ASMase was proven by showing that supplementation with natural eeramide can overcome the resistance of ASMase-deficient hepatocytes to anti-Fas (Paris et ah,... 

Notably, in a study on mouse hepatocytes in vitro, D.A. Brenner and Y.Hannun confirmed that activation of ASMase and generation of eeramide (specifically of chain length Cl6) contributes to TNF-a-induced hepatocyte apoptosis (Osawa et al., 2005), but they did not see an involvement of downstream GD3 formation in their model. Another observation to be mentioned in this context is that TNF-a-induced apoptosis in the human myelogenous leukemia cells was blocked by the ASMase inhibitor SR33557 (Higuchi et al.,... 

In addition to FasL and TNF-a, another TNF-family member, namely TRAIL (= TNF-related apoptosis-inducing ligand) has recently been shown to also depend on ASMase activity in its capability to induce apoptosis. 

E.Gulbins and co-workers showed that TRAIL activates ASMase in... 

Recently, a functional role of ASMase and ceramide in copper-induced apoptosis of hepatocytes and erythrocytes was demonstrated by F. Lang,... 

To summarize, based on the available data, pharmacological inhibition of ASMase might be an opportunity to prevent apoptosis, in particular in the liver, without influencing T-cell apoptosis. In fact, hepatocyte apoptosis is an important element in a number of liver diseases, ranging from cholestatic and alcoholic liver disease to autoimmune and viral hepatitis (Eichhorst, 2005). Furthermore, a role of ASMase-produced ceramide in neuronal and myocardial apoptosis has been implicated from studies in models of rat cerebral and rabbit heart ischemia, respectively (Yu et al., 2000 Argaud et al., 2004) the criticism to the latter two studies is, however, that their conclusion rely on the use of the xanthogenate D609, which inhibits ASMase in an indirect way but certainly is not specific for that enzyme. 

Two studies have implicated a role of ASMase in pathological conditions that involve lung cell apoptosis (i) S. Uhlig and collaborators (Goggel et al.,... 

ASMase-deficient mice are protected in models of lethal endotoxic shock induced by LPS alone (Haimovitz-Friedman et ah, 1997) or LPS after galacto-samine pre-treatment (Garcia-Ruiz et ah, 2003). Also, treatment of mice with the ASMase inhibitor NB6 enhances survival in endotoxemia (Claus et ah,... 

These findings may be readily explained by the role of ASMase in apoptotic cell death, in particular of the endothelium and of hepatocytes. 

Injection of LPS or of the cytokines TNF-a or IL-1(3 into mice increases the activity of Zn -dependent ASMase in the serum (Wong et ah, 2000). Interestingly, serum ASMase activity was seen to be elevated in patients under septic shock, and was found to be negatively correlated with survival (Claus et ah,... 

While ASMase-deficient mice survive lethal doses of LPS (see above), the serum levels of TNF-a-induced by sublethal doses of LPS are similar to those in WT mice (Haimovitz-Friedman et ak, 1997) isolated ASMase-deficient macrophages respond to LPS with a normal pattern of cytokine secretion (Manthey and Schuchman, 1998). Thus, there is no evidence that ASMase is important for LPS-induced inflammatory responses. A recent report showed that imipramine, an inhibitor of cellular ASMase activity, blocked LPS-induced TNF-a secretion from differentiated human monocyte-like THP-1 cells (Cuschieri et ak, 2007). However, in our hands imipramine has no effect on cytokine secretion from these cells or from monocytes isolated from human blood (A.Billich, unpublished observations). 

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