The Disease

The process of target identification analyzes a complex disease process by dissecting it into its fundamental components. This makes it possible to identify the one that is most integral to the manifestation of the disease. Target identification aims to understand the biological processes related to a disease, and to identify its mechanism and the structure of individual elements of the disease. Commonly these individual elements are receptors, enzymes, etc., which become the target of new drugs. 

Beriberi, Thiamine Deficiency. The recognition of vitamins and their importance to the health of human beings came about when Eijkman, a Dutch pathologist, was sent to Java in an attempt to cure an epidemic of beriberi that had appeared in one of the hospitals. Eijkman kept a flock of chickens on the hospital grounds to assist in discovering the disease agent he assumed was involved in the etiology of beriberi. These chickens were fed the scraps from the plates of the hospital patients—primarily poHshed rice, the common food in that part of the world (11). 

Celiac Disease. A disturbance of the lower gastroiatestiaal tract, celiac disease is a chronic disease characterized by loss of appetite and weight, depression and irritabiUty, and diarrhea frequendy followed by constipation (35). One of the more disturbiag features of ceHac disease is the large, frothy, foul-smelling stools. The disease may develop ia childhood or later ia life. Frequendy, the patients who develop the disease ia adulthood report having had some of the symptoms duting childhood. 

The disease takes two different forms depending apparently on whether ergotoxia, the alkaloid ia ergot, attacks predomiaantiy the aervous or the circulatory system. The former coaditioa is characterized by severe coavulsive seizures the latter produces an iatense burning and itching of the skin called St. Anthony s Fire. 

Many human diseases are caused when certain proteins are either over- or underexpressed. Eor example, breast cancer can be induced by overexpressing certain cellular oncogenes within mammary tissue. To study the disease, researchers produce a line of transgenic mice that synthesize an abnormal amount of the same protein. This leads to symptoms of the disease in mice that are similar to what is found in humans. A protein can be overexpressed by inserting a DNA constmct with a strong promotor. Conversely, underexpression of a protein can be achieved by inserting a DNA constmct that makes antisense RNA. This latter blocks protein synthesis because the antisense RNA binds and inactivates the sense mRNA that codes for the protein. Once a line of mice is developed, treatments are studied in mice before these therapies are appHed to humans. 

Secondary immunodeficiencies (9) are much more common than primary ones and frequently occur as a result of immaturity of the immune system in premature infants, immunosuppressive therapy, or surgery and trauma. Illnesses, particularly when prolonged and serious, have been associated with secondary immunodeficiencies, some of which may be reversible. Acquked immune deficiency syndrome (AIDS) (10—12) may be considered a secondary immunodeficiency disease caused by the human immunodeficiency vimses HIV-1 or HIV-2. Hitherto unknown, the disease began to spread in the United States during the latter part of the 1970s. The agent responsible for this infection has been isolated and identified as a retrovims. 

NIDDM is a much more common disease than IDDM, accounting for about 85—90% of all cases of diabetes meUitus. Whereas NIDDM may be present at any age, the incidence increases dramatically with advanced age over 10% of the population reaching 70 years of age has NIDDM. Patients with NIDDM do not require insulin treatment to maintain life or prevent the spontaneous occurrence of diabetic ketoacidosis. Therefore, NIDDM is frequendy asymptomatic and unrecognized, and diagnosis requires screening for elevations in blood or urinary sugar. Most forms of NIDDM are associated with a family history of the disease, and NIDDM is commonly associated with and exacerbated by obesity. The causes of NIDDM are not well understood and there may be many molecular defects which lead to NIDDM. 

Pa.g et s Disease of Bone. Paget s disease, osteitis deformans, occurs mainly ia people over 40. About twice as many men as women are affected. The disease, caused by faulty utilisation of may be mild and asymptomatic requiring Httle or no treatment. Clinical signs are high alkaline phosphatase and high urine hydroxyproline as weU as abnormal bone stmcture which usually goes unrecognised until discovered accidentally by routine x-ray examination (32). 

Phase II. Initial clinical studies for therapeutic safety and efficacy are performed in volunteer patients who are suffering from the disease for which the dmg has therapeutic promise. Recognition of toxic symptoms and side effects are vital at this point because these may occur here, even when not observed in animal studies or in Phase I. 

Stmctural defects at the receptor level are determinant for a number of receptor diseases. In nephrogenic diabetes insipidus, where patients void large volumes of dilute urine even in the presence of vasopressin (antidiuretic hormone) (105), the disease is linked to mutations in three discrete regions of the G-protein-linked vasopressin (V2) receptor (106,107). 

Defects in the LDL receptor have been particularly well explored as a basis of the disease familial hypercholesterolemia (93,111). A number of defects that collectively impair LDL receptor trafficking, binding, or deUvery underHe this disease where LDL and semm cholesterol rise to levels that mediate early cardiovascular mortaUty. Studies of the population distribution of this defect can determine the source of the original mutation. Thus, in Quebec, about 60% of the individuals suffering from familial hypercholesterolemia have a particular 10-kdobase deletion mutation in the LDL gene (112). This may have arisen from an original founder of the French Canadian settiement in the seventeenth century. 

Unfortunately steroids merely suppress the inflammation while the underlying cause of the disease remains. Another serious concern about steroids is that of toxicity. The abmpt withdrawal of glucocorticoid steroids results in acute adrenal insufficiency. Long term use may induce osteoporosis, peptidic ulcers, the retention of fluid, or an increased susceptibiUty to infections. Because of these problems, steroids are rarely the first line of treatment for any inflammatory condition, and their use in rheumatoid arthritis begins after more conservative therapies have failed. 

Asthma affects 3—5% of the population and is one of the most common chronic illnesses (7—9). Both the frequency and severity of asthma appear to be increasing (10—13). Acute, severe asthma has the potential to be fatal. The disease may first appear ia childhood and iadividuals so affected can suffer recurrent episodes throughout their Hves or they may "outgrow" the condition at puberty. On the other hand, there is also adult-onset asthma. These people show no symptoms as children or as young adults, but suddenly develop symptoms later ia life. There have been many reports of bronchial infections preceding the appearance of asthma. However it is not known whether these infections contributed to the development of the disease or whether iadividuals who are already predisposed to asthma ate more likely to experience bronchospasms as a result of a bronchial infection (14). 

In contrast, the total artificial heart (TAH) is designed to overtake the function of the diseased natural heart. While the patient is on heart—lung bypass, the natural ventricles are surgically removed. Polyurethane cuffs are then sutured to the remaining atha and to two other blood vessels that connect with the heart. 

One successful total artificial heart is ABIOMED s electric TAH. This artificial heart consists of two seamless blood pumps which assume the roles of the natural heart s two ventricles (Fig. 7). The pumps and valves are fabricated from a polyurethane, Angioflex. Small enough to fit the majority of the adult population, the heart s principal components are implanted in the cavity left by the removal of the diseased natural heart. A modest sized battery pack carried by the patient suppHes power to the drive system. Miniaturized electronics control the artificial heart which mns as smoothly and quietly as the natural heart. Once implanted, the total artificial heart performs the critical function of pumping blood to the entire body (6). 

The biodistribution of the ideal radiopharmaceutical would show extremely rapid distribution via the circulatory system to the organs of interest and htfle distribution to others. It would be rapidly extracted by the organ or tissue of interest differentially in a way that reflects the disease process of interest. Ideally, abnormahties should be defined by substantial increases in the concentration of the agent because lesions defined by a decrease from surrounding concentrations, ie, cold-spot imaging, are more difficult to image. 

Nuclear medicine studies may reveal information that is primarily anatomic in nature, or indicate the function of an organ on a regional basis (Table 1). These studies may be intended to identify new disease, confirm or deny suspected disease, or foUow the progress of treatment or the course of disease. The diseases may be relatively benign or extremely serious and can range from widespread medical problems such as ischemic heart disease to rarities such as Legge-Perthe s disease and malignant pheochromocytoma (7). 

Composition and Methods of Manufacture. The diseases of diphtheria and tetanus are caused by toxHis synthesized by the organisms CoTynebacterium diphtheriae and Clostridium tetanic respectively. Diphtheria and tetanus vacciaes coataHi purified toxHis that have beea iaactivated by formaldehyde to form toxoids. 

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