CGMP analogs

Gambaryan S, Geiger J, Schwarz UR, Butt E, Begonja A, Obergfell A, Walter U (2004) Potent inhibition of human platelets by cGMP analogs independent of cGMP-dependent protein kinase. Blood 103 2593-600... 

NO is not simply a vasodilator, since, in different preparations of cardiac muscle, endothelium-derived NO as well as NO donors and cGMP analogs appear to enhance myocardial relaxation, decrease diastolic tone, and slightly reduce peak contraction (Shah et al., 1994). The subcellular mechanism of these effects is proposed to be a cGMP-induced reduction in the myofilament response to Ca (Shah etal., 1994). NO-mediated endogenous... 

FIGURE 21-2 Chemical pathways for the synthesis and degradation of cAMP. cAMP is synthesized from ATP by the enzyme adenylyl cyclase with the release of pyrophosphate, and is hydrolyzed into 5 -AMP by the enzyme phosphodiesterase. Both reactions require Mg2. Analogous reactions underlie the synthesis and degradation of cGMP (not shown). PP, inorganic pyrophosphate. 

Like cAMP, 3 -5 -cGMP is widespread as an intracellular messenger substance. Analogous to cAMP, cGMP is formed by catalysis via guanylyl cyclase from GTP (review Lohmaim, 1997). 

Nitric oxide may be the active moiety of STZ that induces diabetes in this animal model. STZ contains a nitroso moiety and may release nitric oxide by a process analogous to the nitric oxide donor compounds SIN-1 and nitroprusside. Turk et al. (1993) have shown that incubation of rat islets with STZ at concentrations that impair insulin secretion results in the generation of nitrite and the accumulation of cGMP. STZ also inhibits mitochondrial aconitase activity of islets to a degree similar to that achieved by IL-1. These findings provide the first evidence that STZ impairs islet function by liberating nittic oxide. 

Unfortunately, there is still much confusion as to what process validation is and what constitutes process validation documentation. At the beginning of this introduction several different definitions for process validation were provided, which were taken from FDA guidelines and the CGMPs. Chapman calls process validation simply organized, documented common sense [6], Others have said that it is more than three good manufactured batches and should represent a lifetime commitment as long as the product is in production, which is pretty much analogous to the retrospective process validation concept. 

As has been demonstrated through X-ray crystallographic analysis [21] with sildenafil (10) and vardenafil (12), the amide moiety forms a bidentate H-bond interaction with Gin 817, analogous to the mode in which the lactam portion of cGMP itself is expected to bind (Figure 9.6). The orientation of the sidechain amide... 

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