The role of bisphosphonates in breast cancer: Development of bisphosphonates

Bisphosphonates are synthetic compounds characterized by a P–C–P group, and are thus analogs of inorganic pyrophosphate. They are used in medicine mainly to inhibit bone resorption in diseases like osteoporosis, Paget's disease and tumor bone disease. They have been used for over a century in industry, and only in 1968 was it shown that bisphosphonates have biological effects. These effects consist mainly of an inhibition of bone resorption and, when given in large amounts, an inhibition of ectopic and normal calcification. While the latter effect is the consequence of a physical-chemical inhibition of calcium phosphate crystal formation, the former is due to a cellular effect involving both apoptosis of the osteoclasts and a destruction of the osteoclastic cytoskeleton, inducing a decrease in osteoclast activity. The biochemical basis of these effects for the nitrogen-containing compounds is an inhibition of the mevalonate pathway caused by the inhibition of farnesylpyrophosphate synthase, which leads to a decrease of the formation of isoprenoid lipids such as farnesylpyrophosphate and geranylgeranylpyrophosphate. The other bisphosphonates are incorporated into the phosphate chain of ATP-containing compounds so that they become non-hydrolyzable. The new P–C–P-containing ATP analogs inhibit cell function and may lead to apoptosis and death of osteoclasts

Effects of adaptation to sea water, 170% sea water and to fresh water on activities and subcellular distribution of branchial Na + −K + -ATPase, low- and high affinity Ca ++ -ATPase, and ouabain-insensitive ATPase in Gillichthys mirabilis

1. Branchial activities of Na + −K + -ATPase, ouabain-insensitive ATPase, (Mg ++ -ATPase) and Ca ++ -ATPase were measured in Gillichthys mirabilis after adaptation to salinities ranging from 170% SW to FW. Stabilities of these activities against freezing and deoxycholate solubilization and the temperature-dependence of activity rates were also investigated. Subcellular distribution and some kinetic properties of these activities, and of SDH were compared in branchial tissues of fish adapted to 170% SW and to FW.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47126/1/360_2004_Article_BF00782593.pd

Diphosphonates and polyphosphates in medicine

Compounds containing phosphorus with P O P bonds (for example PPi) or P C P bonds (diphosphonates) bind strongly to crystals of hydroxyapatite and inhibit their growth and aggregation as well as their rates of dissolution. Both groups of compounds inhibit experimentally induced ectopic calcification in animals. The diphosphonates, which are more stable than PPi, also inhibit bone resorption and bone turnover in various experimental systems; PPi occurs naturally in body fluids and mineralized tissues and may have a physiological function regulating calcification and bone turnover. Abnormalities of PPi metabolism may occur in some human diseases, notably hypophosphatasia and pseudogout. EHDP is able to inhibit ectopic calcification in man, particularly in MOP. It also reduces excessive bone turnover in Paget's disease and excessive bone loss in some types of osteoporosis. 99mTc complexes of EHDP, PPi, and other polyphosphates have recently been used successfully as bone scanning agents. Diphosphonates are therefore not only interesting pharmacological agents for studies of calcium metabolism but are also potentially useful in the investigation and treatment of skeletal disorders in man

Determinants of structure-function relationships among bisphosphonates

Bisphosphonates are a chemical class of compounds in widespread use since the 1970s for the management of disorders of bone metabolism, such as Paget's disease and osteoporosis. The members of this drug class share a common P-C-P backbone structure, where C is carbon and each P is a phosphonate group; the 2 phosphonate groups act as a "bone hook" and are essential for binding to hydroxyapatite. Individual bisphosphonates exhibit differential binding to hydroxyapatite and exert differential actions within osteoclasts. The unique structure of each bisphosphonate determines its efficacy and relative utility in treating specific disorders of bone resorption. The structure-function profile of individual bisphosphonates is determined by the R1 and R2 side groups. Binding to bone is enhanced when R1 is a hydroxyl group. The R2 side group predominantly determines the antiresorptive potency of the bisphosphonates but has some effect on binding. The presence of nitrogen groups within the R2 side group is associated with the ability of an individual bisphosphonate to inhibit farnesyl pyrophosphate (FPP) synthase, a major enzyme in the mevalonate pathway. Structural differences among bisphosphonates explain the observed differences in mineral binding and antiresorptive potency and may in turn account for some of the clinical differences that have been seen in potency, duration of effect, and antifracture efficacy among members of this drug class. © 2007

The vitamin D's in chronic renal failure

summary:We provide a general series form solution for second-order linear PDE system with constant coefficients and prove a convergence theorem. The equations of three dimensional elastic equilibrium are solved as an example. Another convergence theorem is proved for this particular system. We also consider a possibility to represent solutions in a finite form as partial sums of the series with terms depending on several complex variables