Agonist problems

Partial Agonists Problems in Detecting Changes in Efficacy.272... 

PARTIAL AGONISTS PROBLEMS IN DETECTING CHANGES IN EFFICACY... 

From a therapeutic point of view, selective agonists may become useful in the treatment of heart failure and catecholamine-insensitive cardiomyopathy, but only if compounds become available that do not stimulate gastric acid secretion or cause other unforeseen problems. 

Another major second messenger in cells is calcium ion. Virtually any mammalian cell line can be used to measure transient calcium currents in fluorescence assays when cells are preloaded with an indicator dye that allows monitoring of changes in cytosolic calcium concentration. These responses can be observed in real time, but a characteristic of these responses is that they are transient. This may lead to problems with hemi-equilibria in antagonist studies whereby the maximal responses to agonists may be depressed in the presence of antagonists. These effects are discussed more fully in Chapter 6. 

From these studies it is clear that the progression of PAR-based therapy relies upon the future development of new specific agonists and antagonists for PARs 2-4 with much higher potencies than those currently available, with an efficient mode of delivery to target sites. However despite these problems the PARs still rqiresent one of the most attractive therapeutic targets for a number of disease states. 

Importantly, they achieve this without inducing extrapyramidal side-effects or increasing prolactin secretion, which are real problems with neuroleptics. These results have been borne out by preliminary clinical trials of buspirone, used in combination with neuroleptics, and several novel S-HTja agonists (e.g. BSF 190555) are currently under development for this clinical application (Meltzer 1999). 

Withdrawal from opioids is uncomfortable but unlikely to be fatal unless the patient has underlying medical problems. Administer the COWS to determine the severity of withdrawal. Those with a score of 5 or less require no pharmacologic intervention, while those with scores from 6 to 24 are likely to benefit from either a symptoms-based approach or the initiation of buprenorphine. Those with scores greater than 25 should receive either buprenorphine or an alternative full p agonist. 

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