Leonard C. Waite

Bone selective effect of an estradiol conjugate with a novel tetracycline-derived bone-targeting agent

In this study a novel bone-targeting agent containing elements of the tricarbonylmethane system of ring A of tetracycline was developed and was shown to bind to the mineral constituent of bone, hydroxyapatite. Conjugation of this bone-targeting agent to estradiol resulted in a bone-targeted estrogen (BTE(2)-A1) with an enhanced ability to bind to hydroxyapatite. In an ovariectomized rat model of osteoporosis a partial separation of the skeletal effects of estradiol from the uterine effects was observed following subcutaneous administration of BTE(2)-A1. This novel bone-targeting estradiol delivery system has the potential to improve the safety profile of estradiol in the treatment of osteoporosis.

Bone-Targeted Carbonic Anhydrase Inhibitors: Effect of a Proinhibitor on Bone Resorption in Vitro

Abstract Many investigations have indicated a functional role for carbonic anhydrase in the mediation of hormone-stimulated bone resorption. These studies depend heavily on the use of heterocyclic sulfonamide inhibitors of carbonic anhydrase. These drugs have effects on many tissues other than bone, and some of these effects confound the interpretation of studies of the role of carbonic acid in bone metabolism. A novel, “bone-targeted” sulfonamide has been produced to obviate these extraosseous effects. This compound (designated WP-1) is the combination of tetracycline and acetazolamide, such that the acetazolamide is not an active inhibitor. Hydrolysis of WP-1 yields an active carbonic anhydrase inhibitor. WP-1 has a marked affinity for bone mineral, allowing deposition of the drug in bone. At a concentration of 10−5 M, WP-1 attenuates parathyroid hormone stimulated net release of calcium from neonatal rat calvaria in culture. WP-1 is the first member of a class of drugs which may prove useful as pharmacological probes in the study of bone metabolism.

Calcitonin responses in intact and adrenalectomized rats

Abstract The effect of adrenalectomy on the response to exogenously administered calcitonin has been studied in rats. In adrenalectomized rats calcitonin produced a hypocalcemia equivalent to that produced in adrenal intact rats. However, the responses in intact and adrenalectomized rats differed in that recovery from hypocalcemia was delayed by adrenalectomy. Literature data indicate that calcitonin is taken up by the adrenal cortex. Data presented here indicate that adrenal cortical tissue inactivates calcitonin. Thus, the prolongation of the hypocalcemia of calcitonin by adrenalectomy may be due to the removal of an organ that sequesters and degrades the hormone.