Chemistry: analytical and immunological testing – Metal or metal containing – Li – na – k – rb – cs – fr – be – mg – ca – sr – ba – ra
Reexamination Certificate
2001-10-18
2004-11-02
Saucier, Sandra E (Department: 1651)
Chemistry: analytical and immunological testing
Metal or metal containing
Li, na, k, rb, cs, fr, be, mg, ca, sr, ba, ra
C436S087000
Reexamination Certificate
active
06812034
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to modulators of soft tissue calcification. In particular, this invention relates to the discovery that inhibition of bone resorption will also result in the inhibition of calcification of soft tissues.
BACKGROUND OF THE INVENTION
The bisphosphonates have been known to chemists since the middle of the 19th century, when the first synthesis occurred in 1865 in Germany (Menschutkin (1865)
Ann. Chem. Pharm
., 133: 317-320). Bisphosphonates were used in industry, mainly as corrosion inhibitors or as complexing agents in the textile, fertilizer and oil industries. Their ability to inhibit calcium carbonate precipitation, similar to polyphosphates was put to use in the prevention of scaling (Blomen (1995) Pages 111-124 in Bijvoet OLM et al., eds.
Bisphosphonate on Bones
, Elsevier, Amsterdam).
More recently, bisphosphonates have been developed as drugs for use in various diseases of bone, tooth, and calcium metabolism. The bisphosphonates have two fundamental previously known biological effects: inhibition of calcification when given at high doses and inhibition of bone resorption.
Bisphosphonates have been shown to efficiently inhibit ectopic calcification in vivo. Thus, among others, they prevent experimentally induced calcification of many soft tissues when given both parentally and orally (Fleisch et al. (1970)
Eur. J. Clin. Invest
., 1: 12-18; Rosenblum et al. (1977)
Calcif. Tissue Res
., 23: 151-159). In contrast to pyrophosphate, which acts only when given parenterally, bisphosphonates are active when administered orally. They have also been shown to have activity when released locally from various matrices (Levy wet al. (1985)
Science
, 228: 190-192; Golomb et al. (1986)
J. Contr. Rel
., 4: 181-194). In addition, topical administration can lead to a decreased formation of dental calculus (Briner et al. (1971)
Int. Dent. J
. 21: 61-73). This effect is used to prevent tartar formation in humans by the addition of bisphosphonates to toothpastes. In addition, certain bisphosphonates inhibit ectopic ossification when given systemically (Plasmans et al. (1978)
Clin. Orthop
., 132: 233-243) or locally (Ahrengart and Lindgren (1986)
J. Orthop., Res
. 4: 18-26).
Of the bisphosphonates, etidronate has been used in humans to prevent ectopic calcification and ossification. Unfortunately with respect to calcification, the results have been disappointing. In conditions such as scleroderma, dermatomyositis, and calcinosis universalis, the results have proven at best inconclusive (Fleisch (1988) Pages 440-466 in Baker PF (ed)
Handbook of Experimental Pharmacology
, Springer-Verlag, N.Y.). In urolithiasis, the dose that was believed to potentially be effective was such that normal bone mineralization was inhibited (Baumann et al. (1978)
Clin. Sci. Mol. Med
., 54: 509-516). Other reports also describe the effects of bisphosphonates on ectopic ossification, especially fibrodysplasia ossificans progressiva (Reiner et al. (1980) Pages 237-241 in Caniggia A (ed)
Etidronate
. Instituto Gentili, Pisa.), and ossification after spinal cord injury, cranial trauma, and total hip replacement (Slooff et al. (1974)
Acta Orthop. Belg
. 40: 820-828; Finerman and Stover (1981)
Metab. Bone Dis. Relat. Res
., 4: 337-342; Thomas and Amstutz (1985)
J. Bone Joint Surg
. (
Am
) 67: 400-403). While such studies have raised the hope that bisphosphonates might be used clinically to inhibit various types of calcifications, when administered in doses approximating those that inhibit soft tissue calcification, bisphosphonates have impaired the mineralization of normal calcified tissues such as bone and cartilage (King et al. (1971)
Clin. Orthop
., 78: 251-270; Schenk et al. (1973)
Calcif. Tissue Res
., 11: 196-214; Flora et al. (1980)
Metab. Bone Dis. Rel. Res
., 2: 389-407), and, when given in higher amounts, also dentine (Larsson (1974)
Calcif. Tiss. Res
., 16: 109-127), enamel (Ogawa (1980)
Jpn. J. Oral Biol
., 22: 199-226; Weile et al. (1990)
Arch. Oral Biol
., 22: 199-226), and cementum (Alatli and Hammarstrom (1996)
Acta Odontol. Scand
., 54: 59-65).
Moreover, while the different bisphosphonates vary greatly in their activity in bone resorption, they do not vary greatly in the inhibition of mineralization. For most bisphosphonates, the effective daily dose was believed to be on the order of 5-20 mg of compound phosphorus per kg, administered parenterally, suggesting that the bisphosphonates inhibit calcification at high doses via a common mechanism.
Thus, although bisphosphonates have proven successful when administered to humans or other mammals to inhibit bone resorption, the propensity to inhibit the calcification of normal bone when administered at dosages believed high enough to inhibit ectopic calcification, has hampered the therapeutic use of bisphosphonates in the treatment of ectopic calcifications.
SUMMARY OF THE INVENTION
This invention provides new approaches to the treatment of ectopic calcifications and various arterioscleroses (e.g., atherosclerosis). The methods of this invention are premised, in part, on the discovery that agents that inhibit bone resorption will also inhibit ectopic calcification and/or plaque formation and related pathologies associated with arteriosclerosis. Without being bound to a particular theory, it is believed that the process of bone resorption, delivers solubilized calcium (e.g. in a calcium phosphate/protein complex) to the blood where it can travel to sites far removed from bone and there act as a nucleation complex for the formation of ectopic calcifications or atherosclerotic plaques and/or contribute to the formation of an existing calcium deposition.
Various agents, in particular bisphosphonates, are often able to inhibit bone resorption at far lower dosages than the dosages at which they have been observed to inhibit bone calcification. It was believed that the effect on bone resorption was mediated via a biological/cellular mechanism and the effect on bone calcification was mediated by a physio-chemical mechanism (e.g. direct binding to hydroxyapatite). Similarly, it was believed that bisphosphonates could inhibit ectopic calcification by the same physio-chemical mechanism as that used to inhibit bone mineralization. Consequently it was believed that although high dosages of bisphosphonates could inhibit ectopic calcification, this approach had little therapeutic value because of the adverse effect on bone mineralization.
The discovery of this invention, that ectopic calcification can be inhibited by inhibition of bone resorption allows the treatment of pathologies associated with undesired calcification at low dosages, e.g. at dosages that do not adversely effect bone mineralization. Thus, in view of the discoveries described herein, a new therapeutic modality is provided for the alleviation of ectopic calcifications and/or arteriosclerotic plaque formation.
Thus, in one embodiment, this invention provides methods of inhibiting calcification of a soft tissue (e.g., an artery, a heart valve, an atherosclerotic plaque, a cancer, a kidney, a prostate, skin, muscle, cartilage, viscera, and heart muscle) in a mammal. These methods involve inhibiting osteoclastic bone resorption in said mammal (e.g., a mammal diagnosed as having or at risk for a pathology characterized by calcification of a soft tissue) The inhibition is preferably by administration of a bisphosphonate to the mammal in a concentration sufficient to inhibit bone resorption without inhibiting bone mineralization. In preferred embodiments, the bisphosphonate effects a significant reduction of bone resorption at a concentration at least 10-fold, more preferably at least 100-fold, and most preferably at least 1000-fold lower than the concentration at which said bisphosphonate effects a significant reduction of bone mineralization (preferably in the same assay and at the same confidence level). The bisphosphonate may be administered at a dosage at least 10-fold, more preferably at least 100-fold, and most preferably at least 1000-fold low
Hunter Tom
Quine I.P. Law Group PC.
Saucier Sandra E
The Regents of the University of California
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