maxacalcitol and Osteoporosis

A little over two decades ago, the vitamin D activation pathway was elucidated and alfacalcidol arrived on the scene as a prodrug for active vitamin D, 1,25-dihydroxyvitamin D(3), to remedy vitamin D deficiency. With the concurrent reported discovery of the differentiation-inducing effect of active vitamin D, its diverse physiological effects have become appreciated and the research aiming to accentuate selected physiological effects by analog research has made a fresh development. Our studies aimed particularly at separating the differentiation-inducing effect/cell growth-inhibitory effect and the calcemic effect of active vitamin D led to the development of two characteristic analogs, OCT and ED-71. OCT, characterized by its profound differentiation-inducing effect and modest calcemic effect, is currently in practical use as an injectable therapeutic agent for secondary hyperparathyroidism as well as in clinical settings as an ointment for the treatment of psoriasis vulgaris. The other analog, ED-71, possesses a profile inverse to that of OCT and is now under clinical development as an oral preparation for treatment of osteoporosis. The present overview refers to methodology of searching next-generation analogs, exemplifying a new analog, DD-281, based on the knowledge accumulated through development of OCT and ED-71.

Topics: Animals; Calcitriol; Cell Differentiation; Cell Division; Dosage Forms; Drug Design; Humans; Hyperparathyroidism, Secondary; Osteoporosis; Psoriasis; Receptors, Calcitriol; Vitamin D

We have previously reported the merits of chronopharmacological effect of 1-alpha(OH) vitamin D3 in aged stroke-prone spontaneously hypertensive rat (SHRSP), a model of osteoporosis [Eur. J. Pharmacol. 428 (2001) 283.]. In this study, the chronopharmacological effect of 22-oxacalcitriol, a newly developed active vitamin D3 analogue with less calcemic activity, was evaluated by a single and repeated dosing of the drug in aged SHRSP. Animals (7 months old) were kept in rooms with a 12-h light/dark cycle. Single (12.5 microg/kg, i.v.) and repeated (5 microg/kg, i.v. three times a week for 12 weeks) dosing of 22-oxacalcitriol or vehicle was given at either 2 h after lights on (2HALO) or 14 h after lights on (14HALO). The severity of adverse reactions such as the changes of body weight, hypercalcemia and hyperphosphatemia, was significantly mild when the drug was given at 14HALO. Especially, the increase of serum Ca concentration was not detected at 14HALO trial. Serum concentrations of total (protein-bound and unbound) 22-oxacalcitriol and albumin (a major binding protein of the drug) of the 2HALO and 14HALO trials did not significantly differ. The decrease of parathyroid hormone (PTH) concentration was greater in the 14HALO trial while the increase in urinary ratio of Ca to creatinine was greater in the 2HALO trial. The increase in bone density of both femurs at the end of the study was greater in the 14HALO trial. The suppression of urinary excretion of deoxypyridinoline, an index of bone resorption capacity of osteoclast, was greater in the 14HALO trial, which indicates that the efficacy of 22-oxacalcitriol for suppressing bone resorption might vary with the dosing time. This is the first study to show the dosing-time-dependent changes in the efficacy and toxicity of 22-oxacalcitriol in the animal model of osteoporosis. Chronopharmacological differences seem to be more prominent than those of other vitamin D analogues. To use 22-oxacalcitriol at an adequate timing might provide better efficacy and safety than other vitamin D3 analogues for the treatment of osteoporosis.

Topics: Absorptiometry, Photon; Amino Acids; Animals; Body Weight; Bone Density; Calcitriol; Calcium; Creatinine; Dose-Response Relationship, Drug; Male; Osteoporosis; Parathyroid Hormone; Phosphorus; Rats; Rats, Inbred SHR; Serum Albumin; Time Factors