and Japan have evaluated how their governments can facilitate the development of medical products to treat rare disorders. Each has established programs andor policies to support the development of products to address unmet medical needs in small populations and to ensure their citizens access to such essential medicines.Japan implemented an Orphan Product Program in 1993. Australia 's program, initiated in 1998, was developed in collaboration with the United States Food and Drug Administration to facilitate the exchange and review of data on orphan drugs. Canada's assessment, published in 1996, determined that a standalone orphan drug program was not currently warranted, as existing legislation and regulatory policies allow early access to essential medicinal products.In reviewing these programs/policies along with those in the United States and Europe, it is interesting that only Japan designates medical devices as orphan products. Government grants for development are available in the United States, Canada, and Japan. Defined periods of market exclusivity apply in the United States and Europe. Market exclusivity is based on normal patent protection in Australia, Canada, and Japan; however, in Japan the time until generic competition is allowed is primarily defined by the reexamination period, which is extended for orphan products. All the policies allow regulatory fees to be waived or reduced, and a prioriry or accelerated review of the marketing application can usually be expected.

Forskolin, a diterpene which directly stimulates adenylate cyclase, markedly stimulated cAMP production in intact rat parathyroid glands and dispersed cells from hyperplastic and adenomatous human parathyroid tissues. Stimulation of cAMP production in human parathyroid adenomas occurred as early as 2 min and continued for at least 2 h; furthermore, a dose-response relationship was observed, with a maximal 80-fold cAMP response occurring at 100 microM forskolin. When PTH secretion by rat or human parathyroid tissues was studied at low (0.5 mM) and high (2.5 mM) extracellular Ca2+ in either the presence or absence of forskolin, no significant stimulation by forskolin was observed at 15 min, 1 h, and 2 h. When 10 human parathyroid specimens were studied with varying concentrations of forskolin at 1 mM Ca2+, 6 failed to show stimulation of PTH secretion and 4 showed modest but detectable increases in PTH that did not appear dose-related. We conclude that (1) at low and high Ca2+ levels, marked stimulation of cAMP production by forskolin can occur without a corresponding increase in PTH secretion; (2) inhibition of PTH secretion by high extracellular Ca2+ levels continues unchanged despite stimulation of cAMP production by forskolin; and (3) at intermediate Ca2+ levels (1.0 mM), PTH secretion is affected either minimally or not at all by forskolin in human hyperparathyroid tissue preparations. The marked stimulation of parathyroid adenylate cyclase by forskolin without concomitant increases in PTH secretion in the majority of tissues suggests that the level of cAMP production is not a primary or sufficient determinant of hormone secretion.