Calcitriol analogs

Structural modifications of the calcitriol side-chain lead to changes in the biological activity profile of the respective compound series [191]. Introduction of the 22,23-double bond, transposition of the 25-OH group to the 24-position and connection of the terminal methyl groups of the side-chain afforded the so far clinically most relevant calcitriol analog, MC 903, from the Danish pharma manufacturer Leo Pharmaceutical Products [192].MC903has been successfully applied for the topical treatment of psoriasis [193] for a rather long time. 

Calcitriol (Rocaltrol, Calcnex) [Antihypocalcemic/Vitamin D Analog] Uses Reduction of i PTH levels, -iTca on dialysis Action 1,25-Dihydroxycholecalcifool (vit D analog) Dose Adul. Renal failure 0.25 mcg/d PO, t 0.25 mcg/d q4-6wk PRN 0.5 meg 3 x/wk IV, t PRN Hypoparathyroidism ... 

Vitamin D analog of choice for prevention and treatment of renal osteodystrophy less expensive than calcitriol... 

Because of the importance of osteoporosis, the area of vitamin D research has become exceptionally active in the generally quiescent vitamin field. Vitamin D analogs such as calcitriol (8.58, la,25,25-trihydroxycholecalciferol) and other compounds have been suggested as new drugs for these conditions. 

Vitamin Dj analogs alfacalcidol calcitriol choice alciferol... 

Vitamin D is a prohormone that serves as precursor to a number of biologically active metabolites (Figure 42-3). Vitamin D is first hydroxylated in the liver to form 25-hydroxyvitamin D (25[OH]D). This metabolite is further converted in the kidney to a number of other forms, the best studied of which are 1,25-dihydroxyvitamin D (l,25[OH]2D) and 24,25-dihydroxyvitamin D (24,25[OH]2D). Of the natural metabolites, only vitamin D and l,25(OH)2D (as calcitriol) are available for clinical use (Table 42-1). Moreover, a number of analogs of l,25(OH)2D are being synthesized to extend the... 

The liver appears to be the principal organ for clearance. Excess vitamin D is stored in adipose tissue. The metabolic clearance of calcitriol in humans indicates a rapid turnover, with a terminal half-life measured in hours. Several of the l,25(OH)2D analogs are bound poorly by the vitamin D-binding protein. As a result, their clearance is very rapid, with a... 

Two analogs of calcitriol—doxercalciferol and paricalcitol—are approved for the treatment of secondary hyperparathyroidism of chronic kidney disease. Their principal advantage is that they are less likely than calcitriol to induce hypercalcemia for any given reduction in PTH. Their greatest impact is in patients in whom the use of calcitriol may... 

Vitamin D analogs Calcifediol (Calderol) Calcitriol (Rocaltrol) Dihydrotachysterol (DHT, Hytakerol) Ergocalciferol (Calciferol, Drisdol) Generally enhance bone formation by increasing the absorption and retention of calcium and phosphate in the body useful in treating disorders caused by vitamin D deficiency, including hypocalcemia, hypophosphatemia, rickets, and osteomalacia... 

Vitamin D is a precursor for a number of compounds that increase intestinal absorption and decrease renal excretion of calcium and phosphate. Metabolites of vitamin D and their pharmacologic analogs are typically used to increase blood calcium and phosphate levels and to enhance bone mineralization in conditions such as osteodystrophy, rickets, or other situations where people lack adequate amounts of vitamin D. Vitamin D analogs such as calcitriol have also been combined with calcium supplements to help treat postmenopausal osteoporosis,4,9 and to treat bone loss caused by antiinflammatory steroids (glucocorticoids see Chapter 29 28.76 Specific vitamin D-related compounds and their clinical applications are listed in Table 31-5. 

Dihydrotachysterol, an analog of l,25(OH)2D, is also available for clinical use, though it is used much less frequently than calcitriol. Dihydrotachysterol appears to be as effective as calcitriol, differing principally in its time course of action calcitriol increases serum calcium in 1-2 days, whereas dihydrotachysterol requires 1-2 weeks. For an equipotent dose (0.2 mg dihydrotachy-sterol versus 0.5 ug calcitriol), dihydrotachysterol costs about one fourth as much as calcitriol. A disadvantage of dihydrotachysterol is the inability to measure it in serum. Neither dihydrotachysterol nor calcitriol corrects the osteomalacic component of renal osteodystrophy in the majority of patients, and neither should be used in patients with hypercalcemia, especially if the bone disease is primarily osteomalacic. 

The discovery that vitamin D3 (1), also called calciol [I], is actually a pro-hormone and not a vitamin as previously assumed has induced intense worldwide research activities within the last 20 years. Nowadays, it is known that the prohormone is transformed in liver and kidney into physiologically much more active metabolites by hydroxylation. In particular, the la,25-dihy-droxylated derivative, calcitriol (3), performs a key function in the regulation of different physiological events [2]. Some hydroxylated vitamin D derivatives and structural analogs are currently being clinically tested as drugs for the treatment of a range of human diseases such as cancer, psoriasis or immune defects. 

In osteoblasts, keratinocytes, and colonocytes, andpossibly other cells, calcitriol acts via cell surface receptors linked to phospholipase C, resulting in release of diacylglycerol and inositol trisphosphate (Section 14.4.1), followed by opening of intracellular calcium channels and activation of protein kinase C and mitogen-activated protein (MAP) kinases. The effect of this is inhibition of cell proliferation and induction of differentiation. A variety of analogs of calcitriol that do not bind to the nuclear receptor do bind to, and activate, the cell surface receptor, including l,25-dihydroxy-7-dehydrocholesterol and 1,25-dihydroxylumisterol. The rapid nongenomic responses to vitamin D can be demonstrated in knockout mice that lack the vitamin D nuclear receptor (Farach-Carson and Ridall, 1998 Nemere and Farach-Carson, 1998). 

The unique interactions of vitamin D with the VDRs have been a focus of research and have led to the development of vitamin D analogs, which vary in their affinity for this receptor and thus may result in less hypercalcemia, while retaining the positive physiologic actions on bone and parathyroid tissue. Paricalcitol and doxercal-ciferol are D2 compounds which effectively lower PTH in dialysis patients. Paricalcitol differs from calcitriol by the absence of the exocyclic carbon 19 and the fact that it is a vitamin D2 derivative. Currently this analog is available only for IV administration however, an oral formulation is in development. Doxercalciferol, in contrast to calcitriol and paricalcitol, is a prohormone that needs to be hydrox-ylated in the liver to its active 1,25-dihydroxyvitamin D2 product. Doxercalciferol is available for both IV and oral administration. 

When administered at doses ten times that of calcitriol and at a dose equivalent to doxercalciferol, paricalcitol has been less frequently associated with hypercalcemia in animal studies and in human trials. Doxercalciferol has also been associated with a lower incidence of hypercalcemia. While hypercalcemia is less likely, based on differences in selectivity of these analogs for the VDRs, elevated calcium concentrations have been observed with these agents in patients with ESKD. However, some of these cases were associated with excessive dosing of these agents and oversuppression of PTH, a condition more likely to promote hypercalcemia. Limited data are available regarding the use of vitamin D analogs in patients with... 

I Adverse Effects. While all agents are effective in suppressing PTH levels, they differ in the degree to which they cause other metabolic abnormalities. Adverse effects of note with vitamin D therapy in patients treated for sHPT include hypercalcemia and hyperphosphatemia. Differences in calcitriol and vitamin D analogs have been demonstrated in animal studies and in clinical trials evaluating the effect on reduction of PTH while minimizing the risk of these adverse consequences. 

---