Disease, approach

These three schemes of metabolism offer a unique perspective for discussing the analysis of metabolites in clinical chemistry labs. Traditionally, many laboratories have utilized the one analyte, one disease approach to testing. Hence, metabolite A in each of the scenarios would be a single measurement made in a laboratory, often by a relatively nonspecific test such as an immunoassay or fluorometric analysis. There are often numerous circumstances that can produce an elevation of a particular metabolite in addition to an enzyme deficiency produced by a metabolic disease. The result is a false positive. Measurement of more than one metabolite that is affected by a particular enzyme, Phe and Tyr as in the case of phenylketonuria (PKU), reduces the likelihood of a false positive as these amino acids are linked met-abolically. The case is similar in scenarios 2 and 3 where the pattern of metabolites may indicate one or more disorders that share common metabolic pathways. One final point regards scenario 2. Measurements of metabolites 2 or more steps away from the primary metabolic block, theoretically and in practice, are somewhat less reliable indicators of disease than the primary substrate. Often, however, no alternative is presented due to the primary substrate being chemically unstable or difficult to measure analytically. Generally, these metabolites are easier to detect in older infants as they accumulate over time. 

Schork NJ (1997) Genetics of complex disease — approaches, piobltans, and solutions. Am J Respir Crit Care Med 156 S103-S109... 

Studies (4) of uiinaiy extracts analyzed both polarographically after oxidation and by the Callow method with color correction show a good correlation. The values obtained by polarography in the case of women with Addison s disease approach the expected zero level. The polarographic method gave somewhat lower results than the colorimetric and showed less variation in duplicate determinations. 

Pemtz M 1992. Protein Structure. New Approaches to Disease And Therapy. New York, W H Freeman. Schulz G E and R H Schirmer 1979. Principles of Protein Structure. New York, Springer-Verlag. 

The number of known cytokines, as well as the diversity of biological functions, have led to a very complex and often confusing picture of the immunologic and nonimmunologic processes involved. The role of cytokiaes in local or systemic homeostatic mechanisms related to physiological functions may be utilized therapeutically for treatment of cancer and a variety of other diseases (2). Pharmaceutical research and development efforts surrounding lL-1 are typical examples of the cytokine inhibition approach to chronic inflammation research (2). 

Cytokines, eg, interferons, interleukins, tumor necrosis factor (TNF), and certain growth factors, could have antitumor activity directiy, or may modulate cellular mechanisms of antitumor activity (2). Cytokines may be used to influence the proliferation and differentiation of T-ceUs, B-ceUs, macrophage—monocyte, myeloid, or other hematopoietic cells. Alternatively, the induction of interferon release may represent an important approach for synthetic—medicinal chemistry, to search for effective antiinflammatory and antifibrotic agents. Inducers of interferon release may also be useful for lepromatous leprosy and chronic granulomatous disease. The potential cytokine and cytokine-related therapeutic approaches to treatment of disease are summarized in Table 4. A combination of cytokines is a feasible modaUty for treatment of immunologically related diseases however, there are dangers inherent in such an approach, as shown by the induction of lethal disserninated intravascular coagulation in mice adrninistered TNF-a and IFN-y. 

Table 4. Cytokine and Cytokine-Related Therapeutic Approaches to Disease ...

The development of injectable mictocapsules for deUvery of chemotherapy agents remains another active area of research. The ultimate goal is to achieve targeted deUvery of chemotherapy agents to specific sites in the body, ideaUy by injection of dmg-loaded mictocapsules that would seek out and destroy diseased ceUs. Intra-arterial infusion chemotherapy is a direct approach to targeted deUvery. The clinical appHcations of microspheres and mictocapsules in embolization and chemotherapy have been assessed (49) (see Chemotherapeutics, anticancer). 

Melatonin thus could represent a new approach to the physiological control of stress and stress-related infectious diseases (48). 

Tocainide is rapidly and well absorbed from the GI tract and undergoes very fitde hepatic first-pass metabolism. Unlike lidocaine which is - 30% bioavailable, tocainide s availability approaches 100% of the administered dose. Eood delays absorption and decreases plasma levels but does not affect bio availability. Less than 10% of the dmg is bound to plasma proteins. Therapeutic plasma concentrations are 3—9 jig/mL. Toxic plasma levels are >10 fig/mL. Peak plasma concentrations are achieved in 0.5—2 h. About 30—40% of tocainide is metabolized in the fiver by deamination and glucuronidation to inactive metabolites. The metabolism is stereoselective and the steady-state plasma concentration of the (3)-(—) enantiomer is about four times that of the (R)-(+) enantiomer. About 50% of the tocainide dose is efirninated by the kidneys unchanged, and the rest is efirninated as metabolites. The elimination half-life of tocainide is about 15 h, and is prolonged in patients with renal disease (1,2,23). 

As a last example we turn to the world of medicine. Osteo-arthritis is an illness that affects many people as they get older. The disease affects the joints between different bones in the body and makes it hard - and painful - to move them. The problem is caused by small lumps of bone which grow on the rubbing surfaces of the joints and which prevent them sliding properly. The problem can only be cured by removing the bad joints and putting artificial joints in their place. The first recorded hip-joint replacement was done as far back as 1897 - when it must have been a pretty hazardous business - but the operation is now a routine piece of orthopaedic surgery. In fact 30,000 hip joints are replaced in the UK every year world-wide the number must approach half a million. 

S Greenland. Probability logic and probability induction. Epidemiology 9 322-332, 1998. GM Petersen, G Parmigiam, D Thomas. Missense mutations in disease genes A Bayesian approach to evaluate causality. Am J Hum Genet. 62 1516-1524, 1998. 

Perutz, M. Protein Structure New Approaches to Disease and Therapy. New York Freeman, 1992. 

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