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Clinical effects of maxacalcitol on secondary hyperparathyroidism of uremic patients
Clinical Effects of Maxacalcitol on Secondary Hyperparathyroidism of Uremic Patients Tadao Akizawa, MD, PhD, Masashi Suzuki, MD, PhD, Takashi Akiba, MD, PhD, Yoshiki Nishizawa, MD, PhD, and Kiyoshi Kurokawa, MD, PhD ● Maxacalcitol (22-oxacalcitriol [OCT]) is a newly developed vitamin D analogue in Japan. OCT has shown less calcemic action and a strong suppressive effect on parathyroid hormone (PTH) in uremic rats and dogs. In uremic patients with secondary hyperparathyroidism, OCT dose-dependently suppressed PTH secretion and increased serum calcium levels. However, more than 60% of patients achieved a greater than 30% decrease in intact PTH level from baseline with long-term OCT treatment up to 1 year without an unphysiological increase in mean serum calcium levels. Long-term treatment also brought about a reduction in bone metabolic markers, including bone alkaline phosphatase, tartrate-resistant acid phosphatase, and bone gra-protein. These results suggest that although careful attention should be paid to the onset of hypercalcemia and oversuppression of PTH, OCT is one of the effective tools for the treatment of secondary hyperparathyroidism. © 2001 by the National Kidney Foundation, Inc. INDEX WORDS: Maxacalcitol (OCT); 22-oxacalcitriol (OCT); parathyroid hormone (PTH); secondary hyperparathyroidism, uremia.
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HE NUMBER OF long-term dialysis patients managed by dialysis therapy for 10 years or more approached 47,000 at the end of 2000 in Japan. Secondary hyperparathyroidism is known as a representative complication of long-term dialysis patients. It is reported that the risk for parathyroidectomy is increased by 3.9 times in patients on dialysis therapy for 15 to 20 years and 7.3 times in those on dialysis therapy for 20 years or more compared with patients on dialysis therapy for 5 to 10 years.1 This result clearly shows the insufficient effect of the current treatment of secondary hyperparathyroidism. One of the major causes of this insufficient effect is attributable to hypercalcemia resulting from the administration of alfacalcidol or calcitriol. Hypercalcemia inevitably limited the dose of those vitamin D derivatives and calcium salts used as a phosphorus binder. To solve such a problem, various vitamin D analogues with less calcemic action have been developed. Maxacalcitol is one of these vitamin D analogues. STRUCTURE AND CHARACTERISTICS OF MAXACALCITOL
Maxacalcitol is a synthetic analogue of calcitriol. Structurally, the 22nd carbon of calcitriol is exchanged for oxygen in maxacalcitol. Therefore, it was initially named 22-oxacalcitriol (OCT). OCT was found to mimic certain biological actions of calcitriol, such as suppression of tumor and epithelial cell proliferation; differentiation of leukemia, tumor, and epithelial cells; and regulation of the immune system.2,3 Simulta-
neously, it was found that OCT had low calcemic actions, with strong inhibitory effect on parathyroid hormone (PTH) secretion. This characteristic of OCT was first reported by Brown et al4 in normal rats and confirmed by other groups in uremic rats.5,6 Subsequent experiments in uremic rats comparing OCT and calcitriol clarified that the affinity of OCT to vitamin D receptor was 1/8 that of calcitriol, whereas that to vitamin Dbinding protein was 1/500.7,8 The low calcemic action of OCT was also explained by its short plasma half-life and difference in required cofactors for binding to the vitamin D receptor from calcitriol.9 DOSE-FINDING CLINICAL STUDY
OCT was first administered to uremic patients with refractory secondary hyperparathyroidism undergoing hemodialysis three times weekly, and
From the Center of Blood Purification Therapy, Wakayama Medical University, Wakayama; Department of Internal Medicine, Shinrakuen Hospital, Niigata Social Services Organization, Social Welfare Department, Niigata; Department of Blood Purification, Kidney Center, Tokyo Women’s Medical University, Tokyo; Department of Internal Medicine II, Osaka City University Medical School, Osaka; and the School of Medicine, Tokai University, Isehara, Japan. Address reprint requests to Tadao Akizawa, MD, PhD, Center of Blood Purification Therapy, Wakayama Medical University, Kimiidera 811-1, Wakayama, 641-0012, Japan. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3804-0129$35.00/0 doi:10.1053/ajkd.2001.27425
American Journal of Kidney Diseases, Vol 38, No 4, Suppl 1 (October), 2001: pp S147-S151
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an initial OCT dose of 5.5 g was administrated intravenously at the end of every hemodialysis session for 3 weeks.10 The dose of OCT was increased to 11 g from week 3 according to intact PTH and serum calcium levels adjusted for albumin level at week 2. Similarly, the dose was increased to 16.5 g, then 22 g, at every 3-week interval. Criteria for the dose increase were as follows: decrease in intact PTH less than 30% and no hypercalcemia (serum calcium, ⱕ10.5 mg/dL). By the administration of OCT, intact PTH levels began to decrease in the first week and continued to decrease for 12 weeks (Fig 1). The mean intact PTH level at the start of OCT therapy (905.1 ⫾ 66.7 [SE] pg/mL) was reduced to 590.3 ⫾ 73.8 pg/mL after 12 weeks of administration. The mean dose of OCT increased from 5.5 to 11.0 g during this period. Serumadjusted calcium levels measured in individual facilities and one center are shown in Fig 2. Serum calcium levels increased significantly 1 week after the start of OCT therapy, but did not continue to increase; they were maintained within physiological range throughout the study period. Serum calcium level was 10.11 ⫾ 0.1 mg/dL at the start of OCT therapy and 10.81 ⫾ 0.11 mg/dL after 12 weeks. No significant change was
AKIZAWA ET AL
observed in serum phosphorus levels (5.70 ⫾ 0.14 mg/dL at the start of therapy versus 5.95 ⫾ 0.19 mg/dL at the end of OCT therapy) or dose of phosphorus binder. From this dose-titration study, the maximum dosage of OCT was speculated to be less than 20 g per dialysis session. Next, the dosedependent effect of OCT on PTH secretion and serum calcium level was evaluated by a doubleblind study.11 Uremic patients with refractory secondary hyperparathyroidism undergoing hemodialysis three times weekly were randomly allocated into four groups, and OCT doses of 5, 10, or 15 g or placebo were administrated intravenously at the end of every hemodialysis session for 12 weeks. When serum-adjusted calcium levels exceeded 11.5 mg/dL just before the hemodialysis session, administration was discontinued. No significant difference was observed in background factors among the four groups of patients. Intact PTH was significantly suppressed in the OCT groups, but not the placebo group. Among the three OCTtreated groups, the reduction in intact PTH levels was highly dose dependent. Serumadjusted calcium levels significantly increased in the OCT groups, but not the placebo group. Among the three OCT groups, the increase in
Fig 1. Change in intact PTH levels and OCT doses during the dose-titration study. (Reprinted with permission.10)
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Fig 2. Change in serum calcium levels adjusted for albumin and OCT dose during dose-titration study. (Reprinted with permission.10)
serum calcium levels was also highly dose dependent. Considering the relationship between the incidence of hypercalcemic episodes (calcium ⬎ 11.5 mg/dL) within 4 weeks after the start of OCT therapy and baseline intact PTH concentration, initial dose recommendations for OCT were determined as follows: for patients with baseline intact PTH levels less than 500 pg/mL, 5 g per hemodialysis session; and for patients with intact PTH levels of
500 pg/mL or greater, 10 g per hemodialysis session. LONG-TERM CLINICAL STUDY
After determination of the initial dose, longterm effects and safety of OCT were examined. In the long-term study, OCT dose was adjusted by serum calcium and intact PTH levels to avoid hypercalcemia (calcium ⬎ 11.5 mg/dL) and oversuppression of intact PTH (ⱕ150 pg/mL). Fig-
Fig 3. Change in intact PTH levels during the longterm study of OCT administration. Abbreviation: EP2, dose-titration study. (Reprinted with permission.12)
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AKIZAWA ET AL
ure 3 shows the change in intact PTH levels during the 1-year administration study12 that followed the previously mentioned dose-titration study.10 Intact PTH concentrations were suppressed during the period of OCT administration, and a greater than 30% decrease in intact PTH levels from baseline was observed in 62.9% of patients at 12 months. Serum calcium levels also increased, and 18 of 74 patients (24.3%) had at least one episode of hypercalcemia or hypercalcemia-related symptoms. Serum phosphorus levels transiently increased significantly, but returned to preadministration values at the end of the study. According to the decrease in intact PTH levels and increase in serum calcium levels, the dose of OCT was gradually decreased from 8.9 ⫾ 5.9 g at 1 month to 7.0 ⫾ 6.8 g at 12 months. Before the start of OCT administration, bone metabolic markers showed high values, reflecting high-turnover bone disease resulting from secondary hyperparathyroidism. However, by the administration of OCT, plasma levels of bone alkaline phosphatase and tartrate-resistant acid phosphatase were reduced significantly. Bone gra-protein concentration also decreased after the transient increase. These results are compatible with the findings of bone histomorphometric analysis reported by Tsukamoto et al,13 in which they observed a significant decrease in bone formation rate and fibrous tissue volume after 6 months of OCT administration. Oversuppression of PTH by calcitriol and calcitriol per se may contribute to the development of adynamic bone disease. Monier-Faugere et al14 reported in uremic dogs that fibrous bone volume was reduced, but bone turnover was not oversuppressed by OCT. These findings should be further examined in clinical study. ADVERSE EVENTS
OCT was administrated to 977 patients with secondary hyperparathyroidism before approval. Among them, 467 adverse events were observed in 379 cases (38.8%). Major adverse events were hypercalcemia (31.1%), pruritus (5.1%), elevated creatine kinase levels (4.4%), and irritation (1.8%). A strong relation was suspected between hypercalcemia and the onset of pruritus and irritation. No specific elevation was observed in levels of creatine kinase isoenzyme and plasma myoglobin.
In conclusion, although OCT strongly and dose-dependently suppresses PTH secretion in uremic patients with secondary hyperparathyroidism, as do other vitamin D derivatives, careful attention should be paid to the onset of hypercalcemia and oversuppression of PTH. To prove the less calcemic action of OCT clinically, a well-controlled comparative study with intravenous calcitriol is necessary. Furthermore, for severe cases with advanced secondary hyperparathyroidism, the effect of percutaneous direct injection of OCT to the parathyroid gland should be examined as an alternative to intravenous OCT administration. REFERENCES 1. Japanese Society for Dialysis Therapy: An Overview of Regular Dialysis Treatment in Japan as of December 31, 2000. Tokyo, Japan, Japanese Society for Dialysis Therapy, 2001 2. Kubodera N, Watanabe H, Kawanishi T, Matsumoto M: Synthetic studies of vitamin D analogues. XI. Synthesis and differentiation-inducing activity of 1␣, 25-dihydroxy-22oxavitamin D3 analogues. Chem Pharm Bull (Tokyo) 40: 1494-1499, 1992 3. Abe J, Nakamura K, Takita Y, Nakano T, Irie M, Nishii Y: Prevention of immunological disorder in MRL/1 mice by a new synthetic analogue of vitamin D3: 22-oxa-1␣, 25dihydroxyvitamin D3. J Nutr Sci Vitaminol (Tokyo) 36:2131, 1990 4. Brown AJ, Ritter CJ, Finch JL, Morrissey J, Martin KJ, Murayama E, Nishii Y, Slatopolsky E: The noncalcemic analogue of vitamin D, 22-oxacalcitriol suppresses parathyroid hormone synthesis and secretion. J Clin Invest 84:728732, 1989 5. Fukagawa M, Kaname S, Igarashi T, Ogata E, Kurokawa K: Regulation of parathyroid hormone synthesis in chronic renal failure in rats. Kidney Int 39:874-881, 1991 6. Kubrusly M, Gagne ER, Urena P, Hanrotel C, Chabanis S, Lacour B, Drueke TB: Effect of 22-oxa-calcitriol on calcium metabolism in rats with severe secondary hyperparathyroidism. Kidney Int 44:551-556, 1993 7. Denda M, Finch JL, Brown AJ, Nishii Y, Kubodera N, Slatopolsky E: 1,25-Dihydroxyvitamin D3 and 22-oxacalcitriol prevent the decrease in vitamin D receptor content in the parathyroid glands of uremic rats. Kidney Int 50:34-39, 1996 8. Ichikawa F, Hirata M, Endo K, Katsumata K, Ohkawa H, Kubodera N, Fukagawa M, Kurokawa K: Attenuated up-regulation of vitamin D-dependent calcium-binding proteins by 22-oxa-1, 25-dihydroxyvitamin D3 in uremic rats. A possible mechanism for less-calcemic action. Nephrology 4:391-395, 1998 9. Takeyama K, Masuhiro Y, Fuse H, Endoh H, Murayama A, Kitanaka S, Suzawa M, Yanagisawa J, Kato S: Selective interaction of vitamin D receptor with transcriptional coactivators by a vitamin D analog. Mol Cell Biol 19:1049-1055, 1999
MAXACALCITOL AND UREMIC HYPERPARATHYROIDISM
10. Kurokawa K, Akizawa T, Suzuki M, Akiba T, Ogata E, Slatopolsky E: Effect of 22-oxacalcitriol injection for treatment of secondary hyperparathyroidism in renal insufficiency patients undergoing dialysis [Japanese]. Kidney Dial 47:715-737, 1999 11. Akizawa T, Kurokawa K, Suzuki M, Akiba T, Nishizawa Y, Ohashi Y, Ogata E, Slatopolsky E: Suppressive effect of 22-oxacalcitriol on secondary hyperparathyroidism of hemodialysis patients. A double blind comparison among four doses. J Am Soc Nephrol 7:1810A, 1996 (abstr) 12. Kurokawa K, Akizawa T, Suzuki M, Akiba T, Ogata E, Slatopolsky E: Effect of long-term administration of
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22-oxacalcitriol on secondary hyperparathyroidism in hemodialysis patients [Japanese]. Kidney Dial 48:243-264, 2000 13. Tsukamoto Y, Hanaoka M, Matsuo T, Saruta T, Nomura M, Takahashi Y: Effect of 22-oxacalcitriol on bone histology of hemodialyzed patients with severe secondary hyperparathyroidism. Am J Kidney Dis 35:458464, 2000 14. Monier-Faugere MC, Geng Z, Friedler RM, Qi Q, Kubodera N, Slatopolsky E, Malluche HH: 22-Oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure. Kidney Int 55:821-832, 1999
T
HE NUMBER OF long-term dialysis patients managed by dialysis therapy for 10 years or more approached 47,000 at the end of 2000 in Japan. Secondary hyperparathyroidism is known as a representative complication of long-term dialysis patients. It is reported that the risk for parathyroidectomy is increased by 3.9 times in patients on dialysis therapy for 15 to 20 years and 7.3 times in those on dialysis therapy for 20 years or more compared with patients on dialysis therapy for 5 to 10 years.1 This result clearly shows the insufficient effect of the current treatment of secondary hyperparathyroidism. One of the major causes of this insufficient effect is attributable to hypercalcemia resulting from the administration of alfacalcidol or calcitriol. Hypercalcemia inevitably limited the dose of those vitamin D derivatives and calcium salts used as a phosphorus binder. To solve such a problem, various vitamin D analogues with less calcemic action have been developed. Maxacalcitol is one of these vitamin D analogues. STRUCTURE AND CHARACTERISTICS OF MAXACALCITOL
Maxacalcitol is a synthetic analogue of calcitriol. Structurally, the 22nd carbon of calcitriol is exchanged for oxygen in maxacalcitol. Therefore, it was initially named 22-oxacalcitriol (OCT). OCT was found to mimic certain biological actions of calcitriol, such as suppression of tumor and epithelial cell proliferation; differentiation of leukemia, tumor, and epithelial cells; and regulation of the immune system.2,3 Simulta-
neously, it was found that OCT had low calcemic actions, with strong inhibitory effect on parathyroid hormone (PTH) secretion. This characteristic of OCT was first reported by Brown et al4 in normal rats and confirmed by other groups in uremic rats.5,6 Subsequent experiments in uremic rats comparing OCT and calcitriol clarified that the affinity of OCT to vitamin D receptor was 1/8 that of calcitriol, whereas that to vitamin Dbinding protein was 1/500.7,8 The low calcemic action of OCT was also explained by its short plasma half-life and difference in required cofactors for binding to the vitamin D receptor from calcitriol.9 DOSE-FINDING CLINICAL STUDY
OCT was first administered to uremic patients with refractory secondary hyperparathyroidism undergoing hemodialysis three times weekly, and
From the Center of Blood Purification Therapy, Wakayama Medical University, Wakayama; Department of Internal Medicine, Shinrakuen Hospital, Niigata Social Services Organization, Social Welfare Department, Niigata; Department of Blood Purification, Kidney Center, Tokyo Women’s Medical University, Tokyo; Department of Internal Medicine II, Osaka City University Medical School, Osaka; and the School of Medicine, Tokai University, Isehara, Japan. Address reprint requests to Tadao Akizawa, MD, PhD, Center of Blood Purification Therapy, Wakayama Medical University, Kimiidera 811-1, Wakayama, 641-0012, Japan. E-mail: [email protected] © 2001 by the National Kidney Foundation, Inc. 0272-6386/01/3804-0129$35.00/0 doi:10.1053/ajkd.2001.27425
American Journal of Kidney Diseases, Vol 38, No 4, Suppl 1 (October), 2001: pp S147-S151
S147
S148
an initial OCT dose of 5.5 g was administrated intravenously at the end of every hemodialysis session for 3 weeks.10 The dose of OCT was increased to 11 g from week 3 according to intact PTH and serum calcium levels adjusted for albumin level at week 2. Similarly, the dose was increased to 16.5 g, then 22 g, at every 3-week interval. Criteria for the dose increase were as follows: decrease in intact PTH less than 30% and no hypercalcemia (serum calcium, ⱕ10.5 mg/dL). By the administration of OCT, intact PTH levels began to decrease in the first week and continued to decrease for 12 weeks (Fig 1). The mean intact PTH level at the start of OCT therapy (905.1 ⫾ 66.7 [SE] pg/mL) was reduced to 590.3 ⫾ 73.8 pg/mL after 12 weeks of administration. The mean dose of OCT increased from 5.5 to 11.0 g during this period. Serumadjusted calcium levels measured in individual facilities and one center are shown in Fig 2. Serum calcium levels increased significantly 1 week after the start of OCT therapy, but did not continue to increase; they were maintained within physiological range throughout the study period. Serum calcium level was 10.11 ⫾ 0.1 mg/dL at the start of OCT therapy and 10.81 ⫾ 0.11 mg/dL after 12 weeks. No significant change was
AKIZAWA ET AL
observed in serum phosphorus levels (5.70 ⫾ 0.14 mg/dL at the start of therapy versus 5.95 ⫾ 0.19 mg/dL at the end of OCT therapy) or dose of phosphorus binder. From this dose-titration study, the maximum dosage of OCT was speculated to be less than 20 g per dialysis session. Next, the dosedependent effect of OCT on PTH secretion and serum calcium level was evaluated by a doubleblind study.11 Uremic patients with refractory secondary hyperparathyroidism undergoing hemodialysis three times weekly were randomly allocated into four groups, and OCT doses of 5, 10, or 15 g or placebo were administrated intravenously at the end of every hemodialysis session for 12 weeks. When serum-adjusted calcium levels exceeded 11.5 mg/dL just before the hemodialysis session, administration was discontinued. No significant difference was observed in background factors among the four groups of patients. Intact PTH was significantly suppressed in the OCT groups, but not the placebo group. Among the three OCTtreated groups, the reduction in intact PTH levels was highly dose dependent. Serumadjusted calcium levels significantly increased in the OCT groups, but not the placebo group. Among the three OCT groups, the increase in
Fig 1. Change in intact PTH levels and OCT doses during the dose-titration study. (Reprinted with permission.10)
MAXACALCITOL AND UREMIC HYPERPARATHYROIDISM
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Fig 2. Change in serum calcium levels adjusted for albumin and OCT dose during dose-titration study. (Reprinted with permission.10)
serum calcium levels was also highly dose dependent. Considering the relationship between the incidence of hypercalcemic episodes (calcium ⬎ 11.5 mg/dL) within 4 weeks after the start of OCT therapy and baseline intact PTH concentration, initial dose recommendations for OCT were determined as follows: for patients with baseline intact PTH levels less than 500 pg/mL, 5 g per hemodialysis session; and for patients with intact PTH levels of
500 pg/mL or greater, 10 g per hemodialysis session. LONG-TERM CLINICAL STUDY
After determination of the initial dose, longterm effects and safety of OCT were examined. In the long-term study, OCT dose was adjusted by serum calcium and intact PTH levels to avoid hypercalcemia (calcium ⬎ 11.5 mg/dL) and oversuppression of intact PTH (ⱕ150 pg/mL). Fig-
Fig 3. Change in intact PTH levels during the longterm study of OCT administration. Abbreviation: EP2, dose-titration study. (Reprinted with permission.12)
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AKIZAWA ET AL
ure 3 shows the change in intact PTH levels during the 1-year administration study12 that followed the previously mentioned dose-titration study.10 Intact PTH concentrations were suppressed during the period of OCT administration, and a greater than 30% decrease in intact PTH levels from baseline was observed in 62.9% of patients at 12 months. Serum calcium levels also increased, and 18 of 74 patients (24.3%) had at least one episode of hypercalcemia or hypercalcemia-related symptoms. Serum phosphorus levels transiently increased significantly, but returned to preadministration values at the end of the study. According to the decrease in intact PTH levels and increase in serum calcium levels, the dose of OCT was gradually decreased from 8.9 ⫾ 5.9 g at 1 month to 7.0 ⫾ 6.8 g at 12 months. Before the start of OCT administration, bone metabolic markers showed high values, reflecting high-turnover bone disease resulting from secondary hyperparathyroidism. However, by the administration of OCT, plasma levels of bone alkaline phosphatase and tartrate-resistant acid phosphatase were reduced significantly. Bone gra-protein concentration also decreased after the transient increase. These results are compatible with the findings of bone histomorphometric analysis reported by Tsukamoto et al,13 in which they observed a significant decrease in bone formation rate and fibrous tissue volume after 6 months of OCT administration. Oversuppression of PTH by calcitriol and calcitriol per se may contribute to the development of adynamic bone disease. Monier-Faugere et al14 reported in uremic dogs that fibrous bone volume was reduced, but bone turnover was not oversuppressed by OCT. These findings should be further examined in clinical study. ADVERSE EVENTS
OCT was administrated to 977 patients with secondary hyperparathyroidism before approval. Among them, 467 adverse events were observed in 379 cases (38.8%). Major adverse events were hypercalcemia (31.1%), pruritus (5.1%), elevated creatine kinase levels (4.4%), and irritation (1.8%). A strong relation was suspected between hypercalcemia and the onset of pruritus and irritation. No specific elevation was observed in levels of creatine kinase isoenzyme and plasma myoglobin.
In conclusion, although OCT strongly and dose-dependently suppresses PTH secretion in uremic patients with secondary hyperparathyroidism, as do other vitamin D derivatives, careful attention should be paid to the onset of hypercalcemia and oversuppression of PTH. To prove the less calcemic action of OCT clinically, a well-controlled comparative study with intravenous calcitriol is necessary. Furthermore, for severe cases with advanced secondary hyperparathyroidism, the effect of percutaneous direct injection of OCT to the parathyroid gland should be examined as an alternative to intravenous OCT administration. REFERENCES 1. Japanese Society for Dialysis Therapy: An Overview of Regular Dialysis Treatment in Japan as of December 31, 2000. Tokyo, Japan, Japanese Society for Dialysis Therapy, 2001 2. Kubodera N, Watanabe H, Kawanishi T, Matsumoto M: Synthetic studies of vitamin D analogues. XI. Synthesis and differentiation-inducing activity of 1␣, 25-dihydroxy-22oxavitamin D3 analogues. Chem Pharm Bull (Tokyo) 40: 1494-1499, 1992 3. Abe J, Nakamura K, Takita Y, Nakano T, Irie M, Nishii Y: Prevention of immunological disorder in MRL/1 mice by a new synthetic analogue of vitamin D3: 22-oxa-1␣, 25dihydroxyvitamin D3. J Nutr Sci Vitaminol (Tokyo) 36:2131, 1990 4. Brown AJ, Ritter CJ, Finch JL, Morrissey J, Martin KJ, Murayama E, Nishii Y, Slatopolsky E: The noncalcemic analogue of vitamin D, 22-oxacalcitriol suppresses parathyroid hormone synthesis and secretion. J Clin Invest 84:728732, 1989 5. Fukagawa M, Kaname S, Igarashi T, Ogata E, Kurokawa K: Regulation of parathyroid hormone synthesis in chronic renal failure in rats. Kidney Int 39:874-881, 1991 6. Kubrusly M, Gagne ER, Urena P, Hanrotel C, Chabanis S, Lacour B, Drueke TB: Effect of 22-oxa-calcitriol on calcium metabolism in rats with severe secondary hyperparathyroidism. Kidney Int 44:551-556, 1993 7. Denda M, Finch JL, Brown AJ, Nishii Y, Kubodera N, Slatopolsky E: 1,25-Dihydroxyvitamin D3 and 22-oxacalcitriol prevent the decrease in vitamin D receptor content in the parathyroid glands of uremic rats. Kidney Int 50:34-39, 1996 8. Ichikawa F, Hirata M, Endo K, Katsumata K, Ohkawa H, Kubodera N, Fukagawa M, Kurokawa K: Attenuated up-regulation of vitamin D-dependent calcium-binding proteins by 22-oxa-1, 25-dihydroxyvitamin D3 in uremic rats. A possible mechanism for less-calcemic action. Nephrology 4:391-395, 1998 9. Takeyama K, Masuhiro Y, Fuse H, Endoh H, Murayama A, Kitanaka S, Suzawa M, Yanagisawa J, Kato S: Selective interaction of vitamin D receptor with transcriptional coactivators by a vitamin D analog. Mol Cell Biol 19:1049-1055, 1999
MAXACALCITOL AND UREMIC HYPERPARATHYROIDISM
10. Kurokawa K, Akizawa T, Suzuki M, Akiba T, Ogata E, Slatopolsky E: Effect of 22-oxacalcitriol injection for treatment of secondary hyperparathyroidism in renal insufficiency patients undergoing dialysis [Japanese]. Kidney Dial 47:715-737, 1999 11. Akizawa T, Kurokawa K, Suzuki M, Akiba T, Nishizawa Y, Ohashi Y, Ogata E, Slatopolsky E: Suppressive effect of 22-oxacalcitriol on secondary hyperparathyroidism of hemodialysis patients. A double blind comparison among four doses. J Am Soc Nephrol 7:1810A, 1996 (abstr) 12. Kurokawa K, Akizawa T, Suzuki M, Akiba T, Ogata E, Slatopolsky E: Effect of long-term administration of
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22-oxacalcitriol on secondary hyperparathyroidism in hemodialysis patients [Japanese]. Kidney Dial 48:243-264, 2000 13. Tsukamoto Y, Hanaoka M, Matsuo T, Saruta T, Nomura M, Takahashi Y: Effect of 22-oxacalcitriol on bone histology of hemodialyzed patients with severe secondary hyperparathyroidism. Am J Kidney Dis 35:458464, 2000 14. Monier-Faugere MC, Geng Z, Friedler RM, Qi Q, Kubodera N, Slatopolsky E, Malluche HH: 22-Oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure. Kidney Int 55:821-832, 1999