Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1997-02-20
2003-07-08
Romeo, David S. (Department: 1647)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C530S327000, C530S328000, C530S329000, C530S330000
Reexamination Certificate
active
06589750
ABSTRACT:
BACKGROUND OF THE INVENTION
(i) Field of the Invention
The present invention pertains to the therapeutic use of a peptide molecule derived from maturation products of SMR1 (Submandibular rat protein 1).
(ii) Description of the Related Art
The intracellular or systemic hydro-mineral imbalance of the body of a mammal, and more specifically of the human body is the cause of multiple pathologies affecting the metabolism and the physiological behavior of diverse organs and tissues, such as bone, kidney, parathyroid, pancreas, intestine, the glandular mucosa of the stomach or the prostate as well as salivary glands.
In the body of a mammal, the maintenance of the transmembrane potassium/sodium and magnesium/calcium ratios is critically important in the control of cell excitation and the regulation of many aspects of intracellular metabolism. The most active tissues such as nerve, liver and muscle have a higher ratio of potassium/sodium and magnesium/calcium than inactive tissues such as skin and erythrocytes. In addition, the most active tissues have a higher phosphorus content than inactive tissues, in keeping with the role of phosphate esters in cellular energy metabolism.
An adult human contains approximately 1,000 g of calcium (Krane et al., 1970). Some 99% of this calcium is in the skeleton in the form of hydroxyapatite, and 1% is contained in the extracellular fluids and soft tissues. About 1% of the skeletal content of calcium is freely exchangeable with the extracellular fluids. Although small as a percentage of skeletal content, this exchangeable pool is approximately equal to the total content of calcium in the extracellular fluids and soft tissues, and serves as an important buffer or storehouse of calcium. Thus, calcium plays two predominant physiological roles in the organism. In bone, calcium salts provide the structural integrity of the skeleton. In the extracellular fluids and in the cytosol, the concentration of calcium ions is critically important in the maintenance and control of a number of biochemical processes, and the concentrations of Ca
2+
in both compartments are maintained with great constancy (Broadus, 1993). Other important mineral ions such as sodium, magnesium or phosphorus are deeply involved in the mineral ion balance necessary for a good intra- and extra-cellular metabolism. The term mineral ion balance refers to the state of mineral homeostasis in the organism vis-à-vis the environment. In zero balance, mineral intake and accretion exactly match mineral losses; in positive balance, mineral intake and accretion exceed mineral losses, and in negative balance, mineral losses exceed mineral intake and accretion. Under normal circumstances net calcium absorption provides a surplus of calcium that considerably exceeds systemic requirements.
The extracellular pool of orthophosphate (about 550 mg in human) is in dynamic equilibrium with phosphorus entry and exit via the intestine, bone, kidney and soft tissues. In zero balance, fractional net phosphorus absorption is about two-thirds of phosphorus intake. This amount represents a vast excess over systemic requirements and is quantitatively excreted into the urine.
The extracellular pool of magnesium (about 250 mg in human) is in bidirectional equilibrium with magnesium fluxes across the intestine, bone, kidney and soft tissues. In zero balance, the magnesium derived from the net intestinal absorption (about 100 mg/day in human) represents a systemic surplus and is quantitatively excreted.
Two organs are mainly involved in the absorption and excretion of the different mineral ions of the body: 1) Hormonal and/or intrinsic mechanisms of mineral ion absorption in the intestine provide the body with a mineral supply that exceeds systemic mineral needs by a considerable measure; 2) the renal tubule plays the dominant quantitative role in maintaining normal mineral homeostasis.
Few endogenously produced metabolites have already been shown to participate actively in the maintenance of the mineral ion balance within the body.
The 1,25-dihydroxyvitamin D (also named calcitriol) is the only recognized hormonal stimulus of active intestinal calcium absorption that occurs principally in the duodenum and the jujenum (Lemann Jr J., 1993). As a consequence, reduced net intestinal calcium absorption occurs when either dietary calcium intake is limited, when serum 1,25-dihydroxyvitamin D concentrations are low or when the intestine is unresponsive to this hormone. In contrast, increased intestinal calcium absorption occurs when serum 1,25-dihydroxyvitamin D concentrations are high. Thus defects in the regulation of the 1,25-dihydroxyvitamin D concentration in the serum can cause major disorders reducing or enhancing intestinal calcium absorption and lead to a pathological state. The 1,25-dihydroxyvitamin D also influences the body intake of phosphate.
A second endogenous factor involved in the mineral ion balance is the parathyroid hormone (PTH). Parathyroid hormone regulates the level of calcium, and phosphate in blood by modulating the activity of specific cells in bone and kidney. These actions serve to: 1) stimulate reabsorption of calcium and phosphate from bone; 2) stimulate reabsorption of calcium and inhibit reabsorption of phosphate from glomerular filtrate; and 3) stimulate the renal synthesis of 1,25-dihydroxyvitamin D thereby increasing intestinal absorption of calcium and phosphate.
A third endogenous factor intervening in the mineral ion balance is calcitonin. Calcitonin (CT) is a 32-amino-acid peptide that is secreted primarily by thyroidal C-cells (Deftos, 1993). Its main biological effect is to inhibit osteoclastic bone resorption. This property has led to CT's use for disorders characterized by increased bone resorption, such as Paget's disease, osteoporosis and for the hypercalcemia of malignancy. The secretion of CT is regulated acutely by blood calcium and chronically by gender and perhaps age. Calcitonin is metabolized by the kidney and the liver. The amino acid sequence of CT is widely conserved through the evolution, from fish to mammals.
Defects in the mineral ion balance are the cause of multiple disorders affecting either the bone, the kidney, the intestine, the pancreas, the dental tissues (enamel and ivory), or the stomach mucosa.
A mineral ion imbalance affects the bone remodeling capacity causing disorders such as osteoporosis or affects the bone resorption capacity such as in the hyper-parathyroidism disease. The bone remodeling system has been characterized in numerous publications in the recent past (Parfitt, 1986). Bone remodeling occurs on trabecular and Haversian bone surfaces. The first step is activation of osteoclast precursors to form osteoclasts that then begin to excavate a cavity on a surface. After removal of bone tissues (about 0.05 mm
3
), the site remains quiescent for a short time, following which activation of osteoblast precursors occurs at the site and the excavation is refilled. This process serves several functions, among them the removal of aged, microdamaged bone tissue and rearrangement of the bone architecture to meet the needs of mechanical support. With normal daily use of the skeleton, bone loss, abnormal accumulation of microdamage, or errors in geometry can come about only through defects in this system, for example a defect in the mineral ion balance. Osteoporosis is a major public health concern and there is consequently a great need for new therapeutical molecules that will be able to regulate the mineral ion balance in the body and, if possible, more efficient and more selective (target specific) than the molecules presently used in therapeutic, such as oestrogen and calcitonin. Other bone absorption or resorption diseases may be caused by defects in the renal or gastrointestinal mineral ion metabolism, such as renal osteodystrophy or even caused by a pancreatic insufficiency.
Primary hyperparathyroidism is a very common cause of hypercalcemia, with estimates of incidence as high as 1 in 500 to 1 in 1000 (Bilezikian, 1990). Hyperparathyrois
Rougeon François
Rougeot Catherine
Institut Pasteur
Romeo David S.
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