Human diseases Thrombosis

The use of BRMs to treat human disease has its origins in the use of bacterial toxins to treat cancer by William B. Coley.73 These early studies resulted in the use of microbi-ally-derived substances such as BCG, Picibanil, carbohydrates from plants or fungi such as Krestin and Lentinan, other products such as Biostim and Broncho-Vaxom, as well as thymic extracts (Table 9.4). However, the lot-to-lot variation in the manufacture of these drugs has dampened enthusiasm. Equally, the focus on MOAs in drug development strategies has also dampened developmental efforts. The particulate nature of some BRMs can also result in pulmonary thrombosis and respiratory distress following i.v. injection. However, BRMs are commonly used to treat bladder cancer and derivatives of natural products are routinely used clinically. 

The effects of chronic hypertension on the human organism are, with one exception, of little interest to the investigator studying pathogenesis, although of great import to the sufferer and his physician. That exception is failure of the kidneys. Disease and failure of the heart are probably caused by chronic overstrain, often associated with another metabolic disease, arteriosclerosis of the coronary arteries. They account for about two thirds of the deaths primarily due to hypertension. Strokes of apoplexy, or cerebral vascular accidents, from rupture or thrombosis of a cerebral artery weakened by disease cause another sixth, uremia about one twelfth, and other conditions the remainder (28). Except for uremia, these events are usually the result of overwork and increased arterial tension. Only rarely does the heart escape hypertrophy. 

The determination of cholesterol is important for the diagnosis and prevention of a number of clinical disorders such as hypertension, arteriosclerosis, cerebral thrombosis and coronary heart disease. As the majority of cholesterol in human blood is present in an esterified form, a separate saponification step is required to obtain a total cholesterol analysis early methods for this involved caustic and toxic reagents, long analysis times and a relatively large sample volume. Free cholesterol can be determined chromatographically, although this requires cumbersome and expensive laboratory-based equipment. Modern methods use the enzyme cholesterol esterase to release esterified cholesterol which is then oxidised by a second enzyme, cholesterol oxidase (ChOx, Fig. 23.3) [48]. 

Recombinant human erythropoietin (rHuEpo) may increase the risk of thrombosis (201). It has been reported that patients with carcinoma of the cervix who received chemotherapy and rHuEpo have an increased risk of symptomatic venous thrombosis (201). In clinical trials where the maintenance hematocrit was 3% on PROCRIT clotting of the arteriovenous shunts occurred at an annual rate of about 0.25 events per patient per year. However, other thrombotic conditions such as cerebrovascular events, transient ischemic attacks, myocardial infarction, or pulmonary embolism occurred at a rate of 0,04 events per patient per year (202). In a separate study of I, I I I untreated patients on hemodialysis, clotting of arteriovenous shunts occurred at a rate of 0.5 events per patient per year. In patients with chronic renal failure on hemodialysis who also had congestive heart failure, ischemic heart disease and venous thrombosis were increased in patients who were treated with PROCRIT targeted to a hematocrit level of 42 3% compared to those targeted to 30 3% (202). It has also been reported... 

Thrombosis in stenosed human coronary arteries is one of the most common thrombotic diseases leading to unstable angina, acute myocardial infarction or sudden death. Treatment with angioplasty, thrombolysis, or bypass grafts can expose new thrombogenic surfaces and re-thrombosis may occur. The mechanisms responsible for this process include interactions of platelets with the damaged arterial wall and platelet aggregation. 

When compared to humans, none of the animal species arc predisposed to thrombotic disorders or arterial vascular pathology. Recent studies of in vivo platelet activation and platelet-dependent thrombosis provide evidence that the relationships between intrinsically highly active platelets and thrombotic diseases is not coincidental. 

Several cases of intravenous immunoglobulin-related thrombosis have been reported (78,79). It can be either venous or arterial (80). It has been suggested that thrombosis can be caused by platelet activation and increased plasma viscosity (79). In patients with vascular risk factors, such as old age, hypertension, and a history of stroke or coronary artery disease, complications, such as myocardial infarction, pulmonary embolism, stroke, and acute spinal cord events, have been described (80). Intravenous immunoglobulin enhances platelet aggregation and the release of adenosine triphosphate in human platelets in vitro. In addition, there is a dose-related increase in plasma viscosity with increasing plasma immunoglobulin concentration (79,80). 

Figure 4 shows the allometric plots of pharmacokinetic parameters for the recombinant, soluble, and chimeric form of P-selectin glycoprotein ligand-1 (rPSGL-Ig), an antagonist to P-selectin for the treatment of P-selectin-mediated diseases like thrombosis, reperfusion injury, and deep vein thrombosis. Human rPSGL-Ig pharmacokinetic parameters could accurately be predicted on the basis of data from mouse, rat, monkey, and pig using allometric power functions [54]. 

Specific products from transgenic plants include enkephalins, IFN-a, human serum albumin, glucocerebrosidase, granulocyte macrophage colony-stimulating factor, tti-antit-rypsin inhibitor (for the treatment of CF, liver diseases, hemorrhages) and hirudin (an anticoagulant for the treatment of thrombosis) from the leech Hirudo medicinalis ... 

Rufaihah, A.J., Huang, N.E., lame, S., Lee, J.C., Nguyen, H.N., Byers, B., De, A., Okogbaa, J., Rollins, M., Reijo-Pera, R. Endothelial cells derived from human ipscs increase capillary density and improve perfusion in a mouse model of peripheral arterial disease. Arteriosclerosis, Thrombosis And Vascular Biology 31, e72-e79 (2011)... 

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