Bisphosphonates pamidronate

In other studies, bisphosphonate-pamidronate or alendronate were linked to the terminal carboxylic acid of the stabilized dipeptide Pro-Phe to improve the bioavailability of bisphosphonates by hPepTl-mediated absorption. In-situ single-pass perfused rat intestine studies revealed competitive inhibition of transport by Pro-Phe, suggesting carrier-mediated transport. Oral administration of the dipeptidyl prodrugs resulted in a 3-fold increase in drug absorption following oral administration to rats. The authors suggested that oral bioavailability of bisphosphonates may be improved by PepTl-mediated absorption when administered as peptidyl prodrugs [53]. Future mechanistic studies may prove if hPepTl is involved in the absorption process. 

Bisphosphonates pamidronate, alendronic acid (also see text Drugs Affecting the Episclera, Sclera, and Uvea)... 

Bisphosphonates pamidronate Probable episcleritis, scleritis, uveitis (also, conjunctivitis, blurred vision,... 

Bisphosphonates pamidronate and alendronate (the most active bisphos-phonates approved for clinical use) were converted into the peptidyl prodrugs prolyl-phenylalanylpamidronate [Pro-Phe-pamidonate (420)] and prolyl-phenylalanyl-alendronate [Pro-Phe-alendronate (421)]. It was shown that the bioavailability of bisphosphonates can be enhanced by using the peptide prodrug approach. The increased oral absorption of the prodrugs was reduced by an active carrier-mediated transport. ... 

Cortet B, Flipo RM, Coquerelle P, Duquesnoy B, Delcambre B. Treatment of severe, recalcitrant reflex sympathetic dystrophy assessment of efficacy and safety of the second generation bisphosphonate pamidronate. Chn Rheumatol 1997 16(l) 51-6. 

In comparison with the results obtained with earlier bisphosphonates, clinical trials with the nitrogen-containing bisphosphonate pamidronate in more than 1, 300 patients with cancer have reported greater efficacy without a concomitant increase in renal toxicity. 

Intravenous bisphosphonates (pamidronate, zoled-ronate) have proven very effective in the management of hypercalcemia. These agents potently inhibit osteoclastic bone resorption. Oral bisphosphonates are less effective for treating hypercalcemia. Therefore, pamidronate (Aredia) is given as an intravenous infusion of 60 to 90 mg over 4 to 24 hours. With pamidronate, resolution of hypercalcemia occurs over several days, and the effect usually persists for several weeks. 

Intravenous bisphosphonates (pamidronate, zoledronate) have proven very helpful in the management of hypercalcemia (see below for further discussion of biphosphonates). Typically, a 60-90-mg dose of pamidronate (aredia) is given by intravenous infusion over 4 hours. Alternatively, zoledronate (zometa) can be given in a dose of 4 mg over 15 minutes. Resolution of the hypercalcemia generally occurs within several days and persists for several weeks. 

The remaining two bisphosphonates, pamidronate and zoledronic acid, are approved for treatment of hypercalcemia of malignancy as well as other cancer conditions and will be discussed later in the chapter. 

A multi-centre study [43] carried out a randomised double-blind placebo controlled trial. Patients received a single infusion of 90 mg of pamidronate or placebo (saline) foot temperatures, symptoms and markers of bone turnover (bone-specific alkaline phosphates and deoxypyridinoline cross links) were measured over the 12 months, in ten visits. There results were extremely promising showing bisphosphonate, pamidronate, given as a single dose leads to a reduction in bone turnover. A recent RCT carried out in 2005 [44] concluded that alendronate taken orally 70 mg once weekly over a... 

Bone Metabolism. Figure 3 Chemical structure of pyrophosphate (a) and the bisphosphonates etidronate (b), clodronate (c), pamidronate (d), ibandronate (e). alendronate (f), risedronate (g), zoledronate (h). 

There is considerable interest in using injectable bisphosphonates, such as pamidronate and zoledronic acid, in patients unable to tolerate or absorb oral bisphosphonates. Zoledronic acid in particular has a potential advantage of once-yearly dosing. Currently, neither drug has received FDA approval for this indication. Ibandronate has recently been approved for this indication. 

For women whose breast cancer has metastasized to bone, bisphosphonates are recommended, in addition to chemotherapy or endocrine therapy, to reduce bone pain and fractures.28,64 Pamidronate (90 mg) and zoledronate (4 mg) can be given intravenously once each month. These bisphosphonates are given in combination with calcium and vitamin D. 

Bone disease is a common manifestation of multiple myeloma. Bisphosphonates should be initiated in symptomatic patients with bone lesions to slow osteopenia and reduce the fracture risk associated with the disease. Pamidronate and zolendronic acid have equivalent efficacy in the management of osteolytic lesions, but because of relative ease of administration, zolendronic acid is used most frequently.43 The use of zolendronic acid decreases pain and bone-related complications and improves quality of life. The suggestion that bisphosphonates have direct antimyeloma activity, based on the ability to inhibit NF-kB signaling, remains controversial. Recent cases of osteonecrosis of the jaw have been a major concern. Risk factors are unclear, but osteonecrosis of the jaw is more common in patients receiving intravenous administration of bisphosphonates and having dental procedures performed. It is recommended that patients... 

Pamidronate and zoledronic acid are used most commonly and are potent inhibitors of osteoclast activity.29 The choice of bisphosphonate is a difficult one zoledronic acid is more efficacious in terms of response rate and longer duration of nor-mocalcemia but is approximately four times more expensive.30 Regardless of selection, the bisphosphonates should be administered at diagnosis owing to their delayed onset of action. 

Pamidronate -organic bisphosphonate inhibits bone resorption by osteoclasts -hypotension -syncope -tachycardia -hypocalcemia, hypokalemia, hypomagnesemia -nausea and vomiting rarely... 

Bisphosphonates such as pamidronate and zoledronic acid may prevent skeletal morbidity, such as pathologic fractures and spinal code compression, when used for hormone-refractory prostate cancer in patients with clinically significant bone loss. Usual dosages are pamidronate, 90 mg every month, and zoledronic acid, 4 mg every 3 to 4 weeks. 

The oral absorption of an entirely different class of drugs, namely bisphosphonates, has also been improved by a peptide prodrug strategy [36]. The drugs pamidronate (6.13, n=2) and alendronate (6.13, n=3) were deriv-atized with the Pro-Phe-dipeptidyl unit to yield the prodrugs Pro-Phe-pamidronate (6.14, n=2) and Pro-Phe-alendronate (6.14, n=3), the ob-... 

Bisphosphonates structurally mimic endogenous pyrophosphate, which inhibits precipitation and dissolution of bone minerals. They retard bone resorption by osteoclasts and, in part, also decrease bone mineralizatioa Indications include tumor osteolysis, hypercalcemia, and Paget s disease. Qinical trials with etidronate, administered as an intermittent regimen, have yielded favorable results in osteoporosis. With the newer drugs clodronate, pamidronate, and alendronate, inhibition of osteoclasts predominates a continuous regimen would thus appear to be feasible. 

Pamidronate - Bisphosphonates, including pamidronate, have been associated with renal toxicity manifested as deterioration of renal function and potential renal failure. 

Agents include etidronic acid, pamidronic acid, clodronic acid, alendronic acid, ibandronic acid, rise-dronic acid, zoledronic acid and tiludronic acid. Formulations of clodronic acid and pamidronic acid are available for intravenous administration. The indications for the use of bisphosphonates include treatment of postmenopausal osteoporosis, hypercal-caemia of malignancy and Paget s disease. 

The bisphosphonates are the most effective compounds available to treat hypercalcemia of malignancy. Pamidronate (Aredia) and zoledronic acid (Zometa) can be infused intravenously and are the most effective compounds available for rapid reduction of serum calcium levels. 

Multiple bisphosphonates compounds are available for both oral and intravenous use. Some [alendronate (Fosamax) and etidronate (Didronel)] are used for osteoporosis, others [etidronate, tirludronate (Skelid), risedronate Actonel) for Paget s disease, and yet others [pamidronate Aredia), zoledronic acid] for the hypercalcemia of malignancy. 

Contraindications Hypersensitivity to other bisphosphonates, including alendronate, etidronate, pamidronate, risedronate, and tiludronate inability to stand or sit upright for at least 60 min severe renal impairment with creatinine clearance less than 30 ml/min uncorrected hypocalcemia... 

Contraindications Hypersensitivity to other bisphosphonates, including alendronate, etidronate, pamidronate, risedronate, and tiludronate... 

Bisphosphonates. Bisphosphonates are synthetic compounds designed to function as mimics of pyrophosphate, in which the oxygen atom in P-O-P is replaced with a carbon atom, creating a non-hydrolyzable backbone structure. The bisphosphonates selectively bind to the hydroxyapatite portion of the bone, decreasing the number of sites along the bone surface at which osteoclast-mediated bone resorption can occur. This permits the osteoblasts to lay down well-mineralized new bone without competition from osteoclasts. Clinically employed bisphosphonates include etidronate (8.109), tilu-dronate (8.110), risedronate (8.111), alendronate (8.112), and pamidronate (8.113). 

Bisphosphonates alendronate sodium clodronate disodium etidronate disodium pamidronate disodium risedronate sodium zoledronic acid... 

The bisphosphonates are analogs of pyrophosphate in which the P-O-P bond has been replaced with a nonhydrolyzable P-C-P bond (Figure 42-4). Etidronate, pamidronate, and alendronate have now been joined by risedronate, tiludronate, ibandronate, and zoledronate for clinical use. The bisphosphonates owe at least part of their clinical usefulness and toxicity to their ability to retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system. They localize to regions of bone resorption and so exert their greatest effects on osteoclasts. However, the exact mechanism by which they selectively inhibit bone resorption is not clear. 

The structure of pyrophosphate and of the first three bisphosphonates—etidronate, pamidronate, and alendronate—that were approved for use in the USA. ... 

General Category Bisphosphonates Examples Alendronate (Fosamax) Etidronate (Didronel) Ibandronate (Boniva) Pamidronate (Aredia) Risedronate (Actonel) Treatment Rationale and Principal Indications Appear to block excessive bone resorption and formation is used to normalize bone turnover in conditions such as osteoporosis and Paget disease, and to prevent hypercalcemia resulting from excessive bone resorption in certain forms of cancer... 

The bisphosphonates (also called diphosphonates) are a group of inorganic compounds that include alendronate (Fosamax), pamidronate (Aredia), and several... 

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