Pharmacology pathways

In regard to the experimental evidence available, a substantial number of reports on the chemical constituents of the plant are available, but much less work has been done with the pharmacological properties. Kasture et al., however, made the important observation that a triterpene isolated from R. cordifolia induces anxiety in rodents, an effect accompanied with an increase in serotonin contents in the brain (30). An interesting development from that observation would be to explore further the molecular-pharmacological pathway and the effect of this agent on the serotoninergic system because terpenes, compared with indole alkaloids, are seldom reported for serotoninergic activities. 

Most of the proteins that are used clinically provide pharmaceutical properties that lead to safe and effective therapy for approved therapeutic indications. Some proteins, however, may influence multiple pharmacologic pathways and elicit unwanted effects. An understanding of the specific domains that mediate biologic response permits the engineering of macromolecules that are more specific and less likely to interact with receptors other than the target (see Boxes 4.4 and 4.5). 

Fig. 5. The physiologic and pharmacologic pathway of P2 agonist on [It. XR. This pathway is complex and many signal cascade proteins shown may have relevant genetic variations that may modify sensitivity to pharmacotherapy. (From Johnson M. Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol 2006 117 18-24 with permission.)...

Nicardipine is almost completely absorbed after po adrninistration. Administration of food decreases absorption. It undergoes extensive first-pass metaboHsm in the Hver. Systemic availabiHty is dose-dependent because of saturation of hepatic metaboHc pathways. A 30 mg dose is - 35% bioavailable. Nicardipine is highly protein bound (>95%). Peak plasma concentrations are achieved in 0.5—2.0 h. The principal path of elimination is by hepatic metaboHsm by hydrolysis and oxidation. The metaboHtes are relatively inactive and exert no pharmacological activity. The elimination half-life is 8.6 h. About 60% of the dose is excreted in the urine as metaboHtes (<1% as intact dmg) and 35% as metaboHtes in the feces (1,2,98,99). 

Two important pathways for catecholamine metaboHsm are 0-methylation by COMT, which is cytoplasmicaHy localized, and oxidative deamination by the mitochondrial localized enzyme MAO. There are large amounts of MAO in tissues such as the fiver and the heart which are responsible for the removal of most of the circulating monoamine, including some taken in from the diet. Tyramine is found in high concentrations in certain foods such as cheese, and in wine. Normally, this tyramine is deaminated in the fiver. However, if MAO is inhibited, the tyramine may then be converted into octopamine [104-14-37] which may indirecdy cause release of NE from nerve terminals to cause hypertensive crisis. Thus MAO, which is relatively nonspecific, plays an important role in the detoxification of pharmacologically active amines ingested from the diet. 

Masri B, Knibiehler B, Audigier Y (2005) Apelin signalling a promising pathway from cloning to pharmacology. Cell Signal 17 415-426... 

What are the magnitude and/or pattern of the alteration in a particular pathway in relation to treatments with other compounds (related or unrelated) with known pharmacological or toxicological properties ... 

Components of the JAK-STAT signaling pathway represent novel targets for pharmacological interventions [4]. Recently, a specific and orally active JAK3 antagonist was identified from screening of a chemical library for inhibitors of in vitro JAK3 kinase activity. The most effective compound, CP-690,550, was shown... 

English JM, Cobb MH (2002) Pharmacological inhibitors of MAPK pathways. Trends Pharmacol Sci 23 40—45... 

Since the SUMO pathway affects multiple pathways ranging from transcription, DNA repair, and intracellular trafficking over cell signaling and cell cycle control to basic metabolism, it is not suiprising that links to diseases and viral assaults are emerging. However, the field is not yet at a stage sufficiently developed for pharmacological intervention. Below we will describe selected examples for links of the SUMO pathway to diseases and viral functions. 

---