Study Results in the Clinical Manifestations
Evaluation of range of motion showed that there were improvements in shoulder flexion, elbow extension, and knee extension that increased with time over 104 weeks. Sleep apnea declined 61 by 26 weeks, and the three patients with the most clinically severe sleep apnea all improved. NYHA classifications improved at least one class in all patients by 52 weeks. Visual acuity improved in the three patients with the worst vision. Height and weight growth velocity increased 85 and 131 , respectively,...
Mechanistic Observations from the Clinical Experience
As described above, preclinical studies have suggested several mechanisms by which APC might exert its efficacy in severe sepsis. Analysis of the clinical experience with drotrecogin alfa (activated) has brought about a reexamination of these mechanisms. Pharmacodynamic analyses of data obtained from the phase III study demonstrated that compared to placebo, the administration of drotrecogin alfa (activated) resulted in a significant increase in both prothrombin time (PT) and activated partial...
Therapeutic Hyaluronidases
Testicular hyaluronidase is the principal hyaluronidase used as a therapeutic agent. The enzyme has been extracted from both bovine and ovine testicular tissue and semen. Homogenization followed by centrifugation and precipitation of the supernatant with ammonium sulfate is used to obtain a crude preparation. The enzyme has been further purified to homogeneity by ion-exchange (cation and anion), gel-filtration and affinity (heparin-Sepharose) chromatographies 140 . Bovine testicular...
APC Mechanisms of Action
The protein C pathway was traditionally described as an endothelial-based complex, including TM-thrombin-protein C-protein S that generates the natural anticoagulant APC 60 . Many review articles have been published on the protein C anticoagulation pathway and its role in hemostasis and thrombosis 44,45,61-66 . However, more recently described anti-inflammatory and antiapoptotic properties of APC suggest a role for APC as an endothelial cell or microvascular modulator, with properties in...
Anti Inflammatory and Cytoprotective Mechanisms
The ability of protein C to inhibit thrombin generation could, in and of itself, reduce thrombin-mediated inflammatory effects resulting from decreased thrombin-receptor cleavage, and subsequently reduce platelet and endothelial cell activation (reviewed in 79 ). However, there is growing evidence that APC has direct anti-inflammatory properties (reviewed in 44,45,64-66,80 ), and modulatory effects on cellular functions. APC has been shown in supratherapeutic concentrations to inhibit the...
Enzyme Engineering
2.2 Improving Enzymes by 2.2.1 Rational 2.2.2 Directed 2.2.2.1 Techniques to Generate 2.2.2.2 Screening and 2.2.3 Combining Rational Design and Directed 2.2.4 Other 2.3 Engineered Enzyme 2.3.1 Catalytic 2.3.2 Enzyme 2.3.2.2 Stability in the Presence of Organic 2.3.3 Enzyme 2.3.3.1 Altering Substrate 2.3.3.2 Altered Product 2.3.3.3 New Substrate 2.3.4 Other 2.4 Engineering Therapeutic 2.4.2 Engineering Therapeutic 2.4.2.1 Alteration of Primary AA Sequence 2.4.2.2 Modification of 2.4.2.3 Chemical...
Adverse Effects Interactions and Pharmacokinetics
Dosages of up to 30 mg rhDNase I per day were well tolerated in healthy volunteers and CF patients 69,87 . Severe bronchospasms or anaphylactic reactions, as seen after inhalation of bovine DNase I, have never been observed with rhDNase I. The most common adverse effects reported after daily inhalation of 2.5 mg rhDNase I were voice alterations (hoarseness), pharyngitis, rash, laryngitis, and conjunctivitis 74,76,78 . All these events are generally mild and transient. In patients with severe...
Biochemistry
Early research identified glucosylceramide as the compound that accumulated in Gaucher's cells but it was not until 1965 that the pioneering efforts of Brady, et al. 10,11 in the United States and Patrick 12 in the United Kingdom, revealed that a deficiency of the lysosomal enzyme P-glucocerebrosidase was the defect leading to the accumulation of glucosylceramide in Gaucher Disease. Following the identification of the defective enzyme, it was suggested, as early as 1966 13 that the disease may...
Adverse Reactions and Warnings
The most serious adverse event reported subsequent to Activase administration is bleeding. If serious intracranial, gastrointestinal, retroperitoneal, or pericardial bleeding occurs, treatment must be immediately discontinued. Allergic reactions, including anaphylactoid reactions, laryngeal edema, and urticaria have also been reported. The product should be used with extreme caution in pregnant women, for whom there are no well-controlled studies. Activase has an embryocidal effect in rabbits...
Phase3 Study of Aldurazyme 12721 Study Objectives and Design
Given the results from the phase-1 study, the ability of rhIDU to reduce storage and improve MPS I disease was demonstrated, but these data were not sufficient to obtain registration in the United States. The approval on a single pivotal trial can be achieved based on FDA guidelines, but the type of endpoints, the nature of the control group, the size of the trial, the multiple site design, and the degree of statistical persuasiveness need to be sufficient to meet expectations. Although phase-1...
Safety
Hypersensitivity responses were observed in some patients during infusions but, in general, these responses declined or resolved with continued weekly therapy. One patient had several recurrences of fever and chills and four others had recurrent episodes of urticaria (hives) and, on occasion, symptoms of angioedema (swelling in the tongue or throat). No clinically significant adverse laboratory results were observed in the patients. All patients developed antibodies to the rhIDU the titers...
Lactase
Some enzymes are employed as human digestive aids to replace or increase endogenous digestive enzymatic activities. Lactase and pancreatic enzyme replacement therapies are two such examples. The enzyme P-D-galactoside-galactohydrolase (EC 3.2.1.23), commonly known as P-galactosidase or lactase, hydrolyzes lactose, forming glucose and galactose 165 . Lactose, or milk sugar, is a disaccharide found in the milk of most mammals. Lactose is digested in vivo in the gastrointestinal tract by...
Info
Time (h for uric acid, d for creatinine, calcium, and phosphorus) Time (h for uric acid, d for creatinine, calcium, and phosphorus) FIGURE 8.6 Creatinine, calcium, phosphorus, and uric acid concentration after rasburicase treatment. hyperuricemia avoids strong alkalinization. A high urine pH is associated with decreased phosphate excretion, which can favor the precipitation of calcium-phosphate salts in the renal tubules, a cause of renal failure 46 . By reintroducing an enzyme present in most...
Thrombolytic Therapy in Acute Myocardial Infarction
The beneficial effect of thrombolytic therapy in the treatment of acute myocardial infarction (AMI) is now well established 13-15 . Use of thrombolytic agents has become a standard emergency treatment in such situations to the extent that globally, such drugs are administered to over 500,000 patients each year. It has been estimated that three times that number could potentially benefit from such therapy 5,16 . Although effective, these products achieve complete reperfusion in, on an average,...
Enzymes as Digestive Aids
An array of products, that contain supplemental digestive enzymes are currently in the market. Some of these preparations exhibit a single enzyme activity aimed at degrading a specific dietary substance, while others exhibit multiple enzymatic activities for the degradation of various dietary components. These supplemental enzymes can be used to complement normal digestion, or to provide an additional digestive capacity. Supplemental digestive enzymes are frequently depolymerases that act on...
References
Kreuder, V., et al., Isolation, characterization and crystallization of deoxyribonuclease-I from bovine and rat parotid-gland and its interaction with rabbit skeletal-muscle actin, Eur. J. Biochem., 139, 389-400, 1984. 2. Shiokawa, D. and Tanuma, S., Characterization of human DNase I family endonucleases and activation of DNase gamma during apoptosis, Biochemistry, 40, 143-152, 2001. 3. Evans, C.J. and Aguilera, R.J., DNase II Genes, enzymes and function, Gene, 322, 1-15, 2003. 4. Nadano, D.,...
