**4. Conclusion**

In this chapter, we have developed some PK, PD and PG models , in order to study and monitor the effectiveness, dosage regimen calculation and security of drugs used in psychiatry, by means of Biomarkers of drug concentration in biophase and the incorporation of all the most innovative techniques in pharmacokinetics, pharmacodynamics and pharmacogenetics , which allow us to:


In conclusion, the use of Biomarkers in PK, PD and PG modelling, in continuos developing, has provided us with the adequate tools to choose the best therapeutic strategy and calculate optimal dose, in order to improve the therapeutic drug monitoring of psychiatric drugs, relapses, drug side effects and clinical outcome of the most common psychiatric diseases. http://cpmc.coriell.org/Sections/Medical/DrugsAndGenes\_mp.aspx?PgId=216.

#### **5. References**

170 Biomarker

The GABAergic transmission, may be increased or facilitated, by direct binding of an agonist, such as progesterone, benzodiazepines, barbiturates, to the GABAA receptors and its subsequent activation; by blocking the presynaptic uptake of GABA by Tiagabine; by inhibiting the metabolism of GABA by GABA-transaminase, such as Vigabatrin and Valproate, or by increasing GABA synthesis modulating the enzyme glutamic acid decarboxylase, GAD, responsible for the decarboxylation of glutamate to GABA, as is the case of Gabapentin and other AEDs that enhance the production of GABA and causes a down-regulation of glutamate. For Felbamate, whose exact mechanism is unknown, it is known that exerts its effect on the GABA receptor and by antagonizing the NMDA receptor, while, Topiramato locks the sodium channels of voltage-gated and increases the activity of GABA through the activation of some subtype of GABA receptors, antagonizing some subtype of glutamate receptor and inhibiting the enzyme carbonic anhydrase, particularly

The GH plasma levels, also, have been used as a Surrogate Marker of noradrenergic transmission and, more recently, as evidence of 5HT1a and 5HT1b/d1 receptor activation, being this another example of how one Surrogate Marker serves as measure for very different effects in the CNS (Dinan 1996; Facchinetti et al 1994; Herdman et al 1994;

The GH plasma levels, can serve as a Surrogate Marker for assessing the GABAergic transmission in the CNS and is therefore a useful tool for dosage regimen calculation of the new antiepileptic drugs and for the right choice of therapeutic strategy, since, the oral administration of drugs that facilitates GABAergic transmission, among them the antiepileptics, cause a rise of growth hormone plasma levels, GH, in a dose-dependent manner, being GH release induced by gamma-aminobutyric acid, GABA, and mediated by a dopaminergic mechanism, via dopamine release at suprapituitary level (Cavagnini et al

Thus, eg, Diazepam administration causes a dose-dependent rise in GH and the reached plasmatic peak is related to the plasma level of the drug. This highly significant correlation of the serum concentrations, between GH and Diazepam, has been found, also, with other AEDs, that act via the release or facilitation of GABAergic transmission, so we can use the plasma levels of GH as a Biomarker for dose adjustment of Diazepam, Topiramate, Gabapentin, Oxcarbazepine, Valproate and Levetiracetam, being the optimal dose, that which allow us to achieve the Clinical Surrogate Endpoint of GH equal to 15-25 ng/ml

Once the steady-state and a pharmacological response, ranging between the 20-80% of maximal effect, is reached we can estimate the optimal dose required to achieve the Clinical

In this chapter, we have developed some PK, PD and PG models , in order to study and monitor the effectiveness, dosage regimen calculation and security of drugs used in psychiatry, by means of Biomarkers of drug concentration in biophase and the incorporation

(Monteiro et al 1990; Monteleone et al 1987; Syvälahti & Kanto 1975).

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**3.6.1 PK-PD model** 

**4. Conclusion** 


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**9** 

*USA* 

**A Comparison of Biomarker and** 

Brian T. Luke and Jack R. Collins *SAIC-Frederick, NCI at Frederick, Frederick,* 

**Fingerprint-Based Classifiers of Disease** 

Early detection of a disease is very important since it greatly improves the individual's chance of responding well to treatment. For example, the 5-year survival rate from prostate cancer is nearly 100% if it is detected early [http://www.toacorn.com/news/2005/1027/ Health\_and\_Wellness/077.html]. Similarly, the 5-year survival rate for ovarian cancer is 95% if caught early, but since 75% of the cases are first observed in the later stages of the disease, the overall 5-year survival rate is less than 50% [http://www.information-aboutovarian-cancer.com/]. It would be nice if there was a single test to determine if an individual had cancer somewhere in their body, but unfortunately such a test does not exist. While all cancers have many factors in common, tissue differences and the body's response to different cancers make the test for ovarian cancer (CA125) very different from the test for prostate cancer (PSA). The lack of sufficient sensitivity and specificity has recently resulted in the recommendation that PSA no longer be used as a potential marker of prostate cancer

Even within the same tissue, all cancers are not necessarily the same. It is well known that there are two major types of lung cancer, small cell lung cancer (SCLG) and non-small cell lung cancer (NSCLC). It is also known that NSCLC has three major sub-types; adenocarcinoma (AC), squamous cell carcinoma (SCC), and large cell undifferentiated carcinoma (LCUC). Each of these has differences in the biochemical processes going on within the cancer cell and one should not expect that the detection, or necessarily the treatment, of these cancers will be the same. Of the four recognized forms of lung cancer (SCLG, AC, SCC and LCUC), the latter three are strictly differentiated by appearances of the cell under the microscope. It is possible that the underlying biochemical processes of an AC cell in one individual are significantly different than the biochemical processes in another individual with a cancer that appears similar. Therefore, each of these categories of lung cancer may be composed of one or more states. While the disease category represents the name of the disease based on some experimental observation, the disease state represents a grouping based on the underlying biochemical processes within the diseased cell. The detection of a disease and its treatment should be relative to specific disease states, not a disease category

[http://www.uspreventiveservicestaskforce.org/uspstf/uspsprca.htm].

**1. Introduction** 

**1.1 Early detection of disease** 

or individuals within that category.

